A wide variety of different functions and an impressive array of interactors have been associated with leucine-rich repeat kinase 2 (LRRK2) over the years. Here, I discuss the hypothesis that LRRK2 may be capable of interacting with different proteins at different times and places, therefore, controlling a plethora of diverse functions based on the different complexes formed. Among these, I will then focus on macroautophagy in the general context of the endolysosomal system. First, the relevance of autophagy in Parkinson's disease will be evaluated giving a brief overview of all the relevant Parkinson's disease genes; then, the association of LRRK2 with macroautophagy and the endolysosomal pathway will be analyzed based on the supporting literature.

Introduction

Leucine-rich repeat kinase 2 (LRRK2) is the gene most frequently mutated in familial Parkinson's disease (PD); seven coding mutations characterized by population-specific penetrance (N1437H, R1441G, R1441C, R1441H, Y1699C, G2019S and I2020T) are cause of dominant, late-onset PD [1], while coding and noncoding polymorphisms in the LRRK2 locus are associated with an increased risk of sporadic disease [2]. Interestingly, PD is not the sole disease in which LRRK2 holds genetic relevance. The risk of certain types of cancer appears to be modulated by LRRK2-PD mutations [3]; moreover, noncoding polymorphisms in the LRRK2 locus are associated with an increased risk of leprosy [4] and inflammatory bowel disorder [5]. Of note, though LRRK2 is an ubiquitous gene, its expression is elevated within the immune system, and plays an important role in glia [6], suggesting that tissue homeostasis in health and disease may be regulated by the immune system through LRRK2 activity. The protein product of the LRRK2 gene is an enzyme (∼280 kDa) containing active kinase and GTPase catalytic sites surrounded by protein interaction domains [78]. Over the past 10 years, copious efforts have been dedicated to the dissection of the LRRK2 function and to the search for LRRK2 substrates and interactors.

LRRK2: one protein — multiple partners — multiple functions

A wide variety of different functions have been associated with LRRK2 over the years, including various signaling pathways, autophagy, vesicle trafficking, vesicle recycling at the synapses, protein synthesis, gene expression, mitochondria homeostasis and immune system-specific activities [9]. A bioinformatics survey from our group revealed that 269 putative LRRK2 interactors were published in peer-reviewed journals, and this figure was scaled down to 62 interactors when filters were applied to control for data replication [10]. This scale and variety of putative LRRK2 interactors suggests that LRRK2 may behave as a ‘date-hub’, term that, in systems biology, refers to a dynamic protein capable of forming different complexes at different locations and times [11]. Under this perspective, LRRK2 may be capable of interacting with different proteins, therefore, controlling a plethora of diverse functions based on the complexes formed in different tissues, cell types, stages of development or under specific stimuli [12]. The date-hub hypothesis is intriguing because it provides a plausible reason as to why multiple functions and so many partners have been associated with LRRK2 over the past decade, and why the search for the unique LRRK2 role has revealed challenging. In fact, the concept of just one singular LRRK2 function may be misleading, and the experimental design (cell type, moment in development and experimental conditions) might play a determinant role in how the LRRK2 complex is formed, affecting the function that LRRK2 supports and that the experiment describes. Therefore, more precision is needed in characterizing the model system in which the study of LRRK2 is conducted. Another consequence is that among all the possible LRRK2 functions, only few will be relevant to disease. It will therefore be necessary to define a general group containing all LRRK2 functions among which the smaller subset of disease-associated ones can be identified.

PD and the autophagy–endolysosomal pathway

One of the functions LRRK2 has been associated with is autophagy, in the more general scenario of the endolysosomal system. This specific association is appealing because all the diseases associated with LRRK2 have been, to different extents, related with alterations of autophagy. In the case of PD, this association echoes results of functional studies performed with other PD genes (Figure 1) opening to the possibility that alterations in the autophagy–endolysosomal pathway might be an underlying common mechanism at the base of PD neurodegeneration.

PD genes and autophagy-endolysosomal pathway(s).

Figure 1.
PD genes and autophagy-endolysosomal pathway(s).

Parkinson's disease genes and their possible involvement in autophagy and endolysosomal pathway.

Figure 1.
PD genes and autophagy-endolysosomal pathway(s).

Parkinson's disease genes and their possible involvement in autophagy and endolysosomal pathway.

SNCA was the first gene being associated with PD by either mutations [13] or copy number variations [14]; α-synuclein, the protein product of the SNCA gene, misfolds and deposits as amyloid material forming Lewy bodies, one of the pathological hallmarks of PD. The function of α-synuclein is still not known; it has been suggested that it may exert a chaperone activity at the synapse facilitating vesicle dynamics [15]. Mutated α-synuclein is known to impair chaperone-mediated autophagy (CMA) [16], and it is assumed that a change in the balance between its production and degradation rates may lead to its accumulation during PD. PD genome-wide association studies (PD-GWAS) suggested different candidate genes as risk factors for sporadic PD [17] among which RAB7L1 and cyclin-G-associated kinase (GAK) were further proposed to interact with LRRK2 forming a complex to promote clearance of Golgi-derived vesicles through macroautophagy [18,19].

VPS35 (vacuolar protein sorting-associated protein 35) is mutated in rare forms of familial PD; it is a component of the retromer complex that mediates the distribution of proteins in the endosome–Golgi–lysosome network. Mutations in VPS35 have been associated with alterations in the retromer complex with abnormal trafficking of the autophagy protein ATG9A leading to consequent autophagy impairment [20]. Additional studies showed that loss of (as well as mutations in) VPS35 causes an additional abnormal trafficking of the lysosomal protein LAMP2a (lysosome-associated membrane protein 2), involved in CMA with consequent impairment of α-synuclein degradation [21]. LAMP2a is another protein proposed in the PD-GWAS as a candidate risk factor for sporadic PD [17]; its levels were indeed found to be reduced in the substantia nigra and amygdala of PD cases at a level shown to be sufficient to impair CMA and increase the half-life of α-synuclein [22]. WDR45 (WD repeat domain 45) is a protein mutated in neurodegeneration with brain iron accumulation presenting with Parkinsonism [23]. Only very few studies are available; however, WDR45 has been proposed to control autophagosome elongation [24]. ATP13A2 (ATPase 13A2) is a lysosomal type 5 P-type ATPase mutated in the Kufor-Rakeb syndrome, a juvenile form of Parkinsonism presenting with dementia [25]. Alterations in ATP13A2 have been associated with lysosomal impairment, α-synuclein accumulation and a decrease in cathepsin D activity [26]. Recently, it has been proposed that ATP13A2 may be capable of regulating SYT11 (synaptotagmin 11), another protein identified in PD-GWAS as a possible PD risk factor [18]. The ATP13A2/SYT11 interaction may control lysosomal functionality, autophagy pathways and α-synuclein clearance [27]. GBA (β-glucocerebrosidase) is an enzyme known for its association with Gaucher's disease, a lysosomal storage disorder caused by homozygous mutations reducing the hydrolytic activity of GBA with consequent built-up of undigested, highly toxic glucocerebroside within the lysosomes. Heterozygous mutations in GBA cause a 20-fold increase in the risk of PD [28]. Inhibition of autophagy by inactivation of protein phosphatase 2A (PPP2A) [29] as well as engulfment of the endoplasmic reticulum (ER) with misfolded GBA protein and consequent induction of ER stress [28] were postulated as a causal link between GBA mutations and PD. Recently, GBA mutations (and enzyme deficiency) were associated with a peculiar, final stage of macroautophagy where lysosomes are recycled following the engulfment and digestion of the autophagosomes [30]. Mutations in PINK1, parkin and FBXO7 (F-box only protein 7) lead to early-onset PD; the relevance of these proteins in mitochondria quality control and mitophagy is well established [31]. SYNJ1 (synaptojanin 1) is mutated in rare forms of PD [32]. Although not well studied to date, loss of SYNJ1 causes abnormal endolysosomal trafficking with accumulation of late endosomes and autophagosomes in cone photoreceptors of zebrafish with concomitant defects in autophagosome maturation [33]. Finally, a mutation in SMPD1 (sphingomyelin phosphodiesterase-1), a protein known for its association with Niemann-Pick lysosomal storage disease, was recognized as strong risk factor for PD [34]. SMPD1 is a type of sphingomyelin phosphodiesterase relevant for lysosomal homeostasis [35] and, potentially, autophagy [36].

The alluring scenario of a common pathogenic mechanism connecting all the genes related with PD was further emphasized by the fact that autophagy-deficient mouse models (following Atg7 knockdown) are affected by presynaptic accumulation of α-synuclein, thus recapitulating one of the hallmarks of PD pathogenesis [37].

All this evidence, paired with the fact that macroautophagy constitutes a reasonable therapeutic target with different drugs already approved, has led autophagy and the endolysosomal pathway, among other LRRK2 functions, to gain momentum, becoming the center of attention of many laboratories worldwide.

LRRK2 and the autophagy–endolysosomal pathway

The first reports suggesting a role for LRRK2 in autophagy showed, in cellular models, that overexpression of G2019S-LRRK2 in SHSY5Y cells was sufficient to induce neurite shortening with a mechanism dependent on macroautophagy [38], whereas LRRK2 silencing triggered an increase in the basal macroautophagy flux [39]. These first two works, published between 2008 and 2009, set the stage for many studies that investigated the intriguing, though still incomplete and sometimes controversial, association of LRRK2 with the autophagy–endolysosomal pathway (Figure 2).

LRRK2 and autophagy-endolysosomal pathway(s).

Figure 2.
LRRK2 and autophagy-endolysosomal pathway(s).

LRRK2 and its possible involvement in autophagy and endolysosomal pathway (red boxes = increase, blue boxes = decrease in, autophagy).

Figure 2.
LRRK2 and autophagy-endolysosomal pathway(s).

LRRK2 and its possible involvement in autophagy and endolysosomal pathway (red boxes = increase, blue boxes = decrease in, autophagy).

LRRK2 has been studied in different model systems through overexpression (both wild-type and mutant sequences), knockdown/knockout, chemical inhibition of kinase activity (while increase in kinase activity can normally be achieved by expression of the G2019S-LRRK2 sequence), and in patient-derived cell cultures. As detailed below, the investigation of LRRK2 modulation over macroautophagy has produced a complex and controversial set of results (Table 1) showing (i) both a positive and a negative regulation of LRRK2 over macroautophagy; (ii) a role for LRRK2 in both the initiation and the final phases of autophagy and (iii) similar outcomes following LRRK2 kinase activity inhibition (achieved by chemical inhibition and/or LRRK2 knockdown/knockout) or increase (achieved by overexpression of G2019S-LRRK2).

Table 1
Open challenges for the study of LRRK2 in the context of autophagy-endolysosomal pathway(s)
Discordant reports regarding the role of LRRK2 in macroautophagy Positive and negative regulation of LRRK2 over macroautophagy 
LRRK2 modulation of the initiation and termination phases of macroautophagy 
Similar outcomes following both inhibition and increase of LRRK2 kinase activity 
Technical challenges when integrating reports concerning the role of LRRK2 in macroautophagy Wide variety of model systems (e.g. different cell lines, human vs. animal cells and different types of primary cultures) 
Experiments performed at different LRRK2 expression levels (i.e. overexpression vs. endogenous level) 
Outcomes achieved by studying mutant LRRK2 are difficult to recapitulate with results obtained with the wild-type sequence 
Results obtained with mutant LRRK2 are difficult to summarize; there are too many different mutations (G2019S appears to be the most frequently studied), results are inconsistent showing G2019S-LRRK2 to both potentiate and repress autophagy depending on the model system/experimental procedure. 
Chemical inhibition of LRRK2 kinase activity is difficult to compare with knockdown/knockout strategies where the entire LRRK2 protein is removed (comprising the kinase, GTPase and protein interaction domains) 
Unavailability of drugs and techniques to dissect LRRK2 kinase vs. GTPase activities 
A wide variety of strategies to stimulate/repress macroautophagy coupled with different model systems may result in different macroautophagy pathways and/or control feedback loops to be activated 
Discordant reports regarding the role of LRRK2 in macroautophagy Positive and negative regulation of LRRK2 over macroautophagy 
LRRK2 modulation of the initiation and termination phases of macroautophagy 
Similar outcomes following both inhibition and increase of LRRK2 kinase activity 
Technical challenges when integrating reports concerning the role of LRRK2 in macroautophagy Wide variety of model systems (e.g. different cell lines, human vs. animal cells and different types of primary cultures) 
Experiments performed at different LRRK2 expression levels (i.e. overexpression vs. endogenous level) 
Outcomes achieved by studying mutant LRRK2 are difficult to recapitulate with results obtained with the wild-type sequence 
Results obtained with mutant LRRK2 are difficult to summarize; there are too many different mutations (G2019S appears to be the most frequently studied), results are inconsistent showing G2019S-LRRK2 to both potentiate and repress autophagy depending on the model system/experimental procedure. 
Chemical inhibition of LRRK2 kinase activity is difficult to compare with knockdown/knockout strategies where the entire LRRK2 protein is removed (comprising the kinase, GTPase and protein interaction domains) 
Unavailability of drugs and techniques to dissect LRRK2 kinase vs. GTPase activities 
A wide variety of strategies to stimulate/repress macroautophagy coupled with different model systems may result in different macroautophagy pathways and/or control feedback loops to be activated 

As first, overexpression of LRRK2 suggested a possible involvement in a dual control over macroautophagy and lysosomal functionality by activating macroautophagy through a calcium signaling cascade controlled by the calcium-dependent protein kinase kinase-β (CaMKK-β)/adenosine monophosphate (AMP)-activated protein kinase (AMPK) pathway, and by reducing degradation through a concomitant increase in lysosomal pH [40]. Along the same route, expression of mutant LRRK2 (R1441C, Y1699C and G2019S-LRRK2) in astrocytes resulted in formation of enlarged, but nonfunctional, lysosomes, with altered pH and increased expression of ATP13A2 (in the case of G2019S-LRRK2) [41]. As these defects were rescued by chemical inhibition of LRRK2, the increase in kinase activity following LRRK2 mutation may be responsible for the observed lysosomal alteration. Chemical inhibition of LRRK2 kinase activity confirmed a role for LRRK2 in the modulation of the macroautophagy flux, with apparently discordant results suggesting (i) a positive, mTOR-independent–Beclin-1-dependent [42,43] and (ii) a negative [44] regulation of macroautophagy. Knockdown of LRRK2 (i.e. silencing of its kinase activity) in immune cells resulted in impairment of macroautophagy and reduction of its degradative capacity [45]. However, a similar outcome was obtained in the opposite scenario through overexpression of G2019S-LRRK2 (i.e. increased LRRK2 kinase activity) with disruption of aggregosome formation and impairment in clearance when macroautophagy was assessed concomitantly with proteasome inhibition [46].

Other apparently conflicting results were obtained studying PD patient-derived cells carrying LRRK2 mutations. Studies in mutant fibroblasts suggested both increased based level of macroautophagy through activation of the MEK/ERK pathway (only for G2019S-LRRK2) [47] and reduced response to induction of macroautophagy following nutrient starvation and mTOR inactivation (for R1441G, Y1699C and G2019S-LRRK2) [48]. Neurons derived from PD fibroblasts carrying G2019S-LRRK2 revealed alterations in macroautophagy, however, at the level of autophagosome degradation [49].

LRRK2 animal models did not help in clarifying this complicated landscape. A first LRRK2 knockout mouse model showed a biphasic, age-dependent alteration in macroautophagy in the kidneys [50], whereas transgenic mice expressing G2019S-LRRK2 showed age-dependent degeneration of nigrostriatal pathway and dopaminergic neurons with autophagy and mitochondrial abnormalities [51]. Alongside macroautophagy, CMA has been analyzed as this process was hypothesized to be important for LRRK2 turnover. CMA was found to be impaired by mutant forms of LRRK2 mirroring a mechanism already suggested in the case of mutant α-synuclein [52].

Although the relevance of LRRK2 in the control of autophagy is well documented and accepted by the scientific community, it is clear that we are still missing many mechanistic details while many studies report controversial results in regard to the actual molecular mechanism through which this control is exerted. There may be multiple technical explanations for these inconsistencies (Table 1).

However, in the light of these sometimes confusing data, it may be worth considering again the dynamic ability of LRRK2 to form complexes as it has been previously discussed. In fact, the data-hub hypothesis may not only be relevant to the general array of LRRK2 functions; it may as well describe the role of LRRK2 in the context of autophagy. Different cell types and different triggering circumstances may cause LRRK2 to interact with different partners within the autophagy machinery enabling LRRK2 to control autophagy in slightly different ways. In fact, specific roles for LRRK2 in the control of macroautophagy have been described when LRRK2 was part of specific protein complexes. Particularly, the LRRK2-mediated control of mitochondria homeostasis through macroautophagy was described following interaction with the B-cell lymphoma 2 (Bcl-2) protein [53], and this observation was further corroborated by the finding that Bcl-xL prevented macroautophagy alterations induced by chemical inhibition of LRRK2 kinase activity [54]. LRRK2 promotion of Golgi-derived vesicle clearance by macroautophagy was described only when LRRK2 was in complex with Bcl-2-associated athanogene domain cochaperone 5 (BAG5), GAK and RAB7L1 [18]. Specifically at the presynaptic terminal, LRRK2 was shown to be capable of regulating macroautophagy by phosphorylating EndophilinA, which in turn is capable of modulating the membrane curvature, thus controlling the recruitment of the autophagy machinery to the nascent autophagosome [55].

Conclusion

LRRK2 has been associated with many different functions among which is autophagy. Autophagy has a clear role and impact in LRRK2-associated disorders. Since other PD genes have independently been linked to the autophagy–endolysosomal pathway, this might represent a common mechanism to PD neurodegeneration. However, even if the study of LRRK2 in the context of autophagy has been extensive, the complete picture is still unclear due to controversial results that are very difficult to recapitulate in an exhaustive, unifying hypothesis. I here suggest that, in addition to technical issues, one reason for this plethora of apparently discordant findings can be the specific complex forming behavior of LRRK2. This suggests that, in different experimental systems and cellular models, specific LRRK2 complexes may be formed and not necessarily be involved in the same control/function. Therefore, to understand the dynamic lynchpin activity of LRRK2, we should start shifting the focus of our attention from close-up (i.e. LRRK2 in isolation) to the wider perspective of the experimental context.

Abbreviations

     
  • ATP13A2

    ATPase 13A2;

  •  
  • Bcl-2

    B-cell lymphoma 2;

  •  
  • CaMKK

    calcium-dependent protein kinase kinase-β;

  •  
  • CMA

    chaperone-mediated autophagy;

  •  
  • ER

    endoplasmic reticulum;

  •  
  • ERK

    extracellular signal-regulated kinase;

  •  
  • GAK

    cyclin-G-associated kinase;

  •  
  • GBA

    β-glucocerebrosidase;

  •  
  • LAMP2a

    lysosome-associated membrane protein 2;

  •  
  • LRRK2

    leucine-rich repeat kinase 2;

  •  
  • mTOR

    mammalian target of rapamycin;

  •  
  • PD

    Parkinson's disease;

  •  
  • PD-GWAS

    PD genome-wide association studies;

  •  
  • SMPD1

    sphingomyelin phosphodiesterase-1;

  •  
  • SYNJ1

    synaptojanin 1;

  •  
  • SYT11

    synaptotagmin 11;

  •  
  • VPS35

    vacuolar protein sorting-associated protein 35;

  •  
  • WDR45

    WD repeat domain 45.

Funding

C.M. is supported by an Medical Research Council (MRC) New Investigator Research Grant [MR/L010933/1] awarded to Dr Patrick Lewis and an MRC programme grant [MR/N026004/1] awarded to Prof. John Hardy.

Acknowledgments

I thank Dr Patrick Lewis for helpful discussions and critical reading of the manuscript. I acknowledge generous research support from the Michael J. Fox Foundation, Parkinson's UK and the Rosetrees Trust.

Competing Interests

The Author declares that there are no competing interests associated with this manuscript.

References

References
1
Corti
,
O.
,
Lesage
,
S.
and
Brice
,
A.
(
2011
)
What genetics tells us about the causes and mechanisms of Parkinson's disease
.
Physiol. Rev.
91
,
1161
1218
doi:
2
Hernandez
,
D.G.
,
Reed
,
X.
and
Singleton
,
A.B.
(
2016
)
Genetics in Parkinson disease: Mendelian versus non-Mendelian inheritance
.
J. Neurochem.
139
,
59
74
doi:
3
Agalliu
,
I.
,
San Luciano
,
M.
,
Mirelman
,
A.
,
Giladi
,
N.
,
Waro
,
B.
,
Aasly
,
J.
et al. 
(
2015
)
Higher frequency of certain cancers in LRRK2 G2019S mutation carriers with Parkinson disease: a pooled analysis
.
JAMA Neurol.
72
,
58
65
doi:
4
Wang
,
D.
,
Xu
,
L.
,
Lv
,
L.
,
Su
,
L.-Y.
,
Fan
,
Y.
,
Zhang
,
D.-F.
et al. 
(
2015
)
Association of the LRRK2 genetic polymorphisms with leprosy in Han Chinese from Southwest China
.
Genes Immun.
16
,
112
119
doi:
5
Liu
,
Z.
and
Lenardo
,
M.J.
(
2012
)
The role of LRRK2 in inflammatory bowel disease
.
Cell Res.
22
,
1092
1094
doi:
6
Moehle
,
M.S.
,
Webber
,
P.J.
,
Tse
,
T.
,
Sukar
,
N.
,
Standaert
,
D.G.
,
DeSilva
,
T.M.
et al. 
(
2012
)
LRRK2 inhibition attenuates microglial inflammatory responses
.
J. Neurosci.
32
,
1602
1611
doi:
7
Zimprich
,
A.
,
Biskup
,
S.
,
Leitner
,
P.
,
Lichtner
,
P.
,
Farrer
,
M.
,
Lincoln
,
S.
et al. 
(
2004
)
Mutations in LRRK2 cause autosomal-dominant Parkinsonism with pleomorphic pathology
.
Neuron
44
,
601
607
doi:
8
Paisán-Ruíz
,
C.
,
Jain
,
S.
,
Evans
,
E.W.
,
Gilks
,
W.P.
,
Simón
,
J.
,
van der Brug
,
M.
et al. 
(
2004
)
Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease
.
Neuron
44
,
595
600
doi:
9
Wallings
,
R.
,
Manzoni
,
C.
and
Bandopadhyay
,
R.
(
2015
)
Cellular processes associated with LRRK2 function and dysfunction
.
FEBS J.
282
,
2806
2826
doi:
10
Manzoni
,
C.
,
Denny
,
P.
,
Lovering
,
R.C.
and
Lewis
,
P.A.
(
2015
)
Computational analysis of the LRRK2 interactome
.
PeerJ
3
,
e778
doi:
11
Han
,
J.-D.
,
Bertin
,
N.
,
Hao
,
T.
,
Goldberg
,
D.S.
,
Berriz
,
G.F.
,
Zhang
,
L.V.
et al. 
(
2004
)
Evidence for dynamically organized modularity in the yeast protein-protein interaction network
.
Nature
430
,
88
93
doi:
12
Lewis
,
P.A.
and
Manzoni
,
C.
(
2012
)
LRRK2 and human disease: a complicated question or a question of complexes?
Sci. Signal.
5
,
pe2
doi:
13
Polymeropoulos
,
M.H.
,
Lavedan
,
C.
,
Leroy
,
E.
,
Ide
,
S.E.
,
Dehejia
,
A.
,
Dutra
,
A.
et al. 
(
1997
)
Mutation in the α-synuclein gene identified in families with Parkinson's disease
.
Science
276
,
2045
2047
doi:
14
Singleton
,
A.B.
,
Farrer
,
M.
,
Johnson
,
J.
,
Singleton
,
A.
,
Hague
,
S.
,
Kachergus
,
J.
et al. 
(
2003
)
α-Synuclein locus triplication causes Parkinson's disease
.
Science
302
,
841
doi:
15
Burré
,
J.
,
Sharma
,
M.
,
Tsetsenis
,
T.
,
Buchman
,
V.
,
Etherton
,
M.R.
and
Südhof
,
T.C.
(
2010
)
α-Synuclein promotes SNARE-complex assembly in vivo and in vitro
.
Science
329
,
1663
1667
doi:
16
Cuervo
,
A.M.
,
Stefanis
,
L.
,
Fredenburg
,
R.
,
Lansbury
,
P.T.
and
Sulzer
,
D.
(
2004
)
Impaired degradation of mutant α-synuclein by chaperone-mediated autophagy
.
Science
305
,
1292
1295
doi:
17
Nalls
,
M.A.
,
Pankratz
,
N.
,
Lill
,
C.M.
,
Do
,
C.B.
,
Hernandez
,
D.G.
,
Saad
,
M.
et al. 
(
2014
)
Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease
.
Nat. Genet.
46
,
989
993
doi:
18
Beilina
,
A.
,
Rudenko
,
I.N.
,
Kaganovich
,
A.
,
Civiero
,
L.
,
Chau
,
H.
,
Kalia
,
S.K.
et al. 
(
2014
)
Unbiased screen for interactors of leucine-rich repeat kinase 2 supports a common pathway for sporadic and familial Parkinson disease
.
Proc. Natl. Acad. Sci. U. S. A.
111
,
2626
2631
doi:
19
Dinter
,
E.
,
Saridaki
,
T.
,
Nippold
,
M.
,
Plum
,
S.
,
Diederichs
,
L.
,
Komnig
,
D.
et al. 
(
2016
)
Rab7 induces clearance of α-synuclein aggregates
.
J. Neurochem.
138
,
758
774
doi:
20
Zavodszky
,
E.
,
Seaman
,
M.N.J
,
Moreau
,
K.
,
Jimenez-Sanchez
,
M.
,
Breusegem
,
S.Y.
,
Harbour
,
M.E.
et al. 
(
2014
)
Mutation in VPS35 associated with Parkinson's disease impairs WASH complex association and inhibits autophagy
.
Nat. Commun.
5
,
3828
doi:
21
Tang
,
F.-L.
,
Erion
,
J.R.
,
Tian
,
Y.
,
Liu
,
W.
,
Yin
,
D.-M.
,
Ye
,
J.
et al. 
(
2015
)
VPS35 in dopamine neurons is required for endosome-to-Golgi retrieval of Lamp2a, a receptor of chaperone-mediated autophagy that is critical for α-synuclein degradation and prevention of pathogenesis of Parkinson's disease
.
J. Neurosci.
35
,
10613
10628
doi:
22
Alvarez-Erviti
,
L.
,
Rodriguez-Oroz
,
M.C.
,
Cooper
,
J.M.
,
Caballero
,
C.
,
Ferrer
,
I.
,
Obeso
,
J.A.
et al. 
(
2010
)
Chaperone-mediated autophagy markers in Parkinson disease brains
.
Arch. Neurol.
67
,
1464
1472
doi:
23
Haack
,
T.B.
,
Hogarth
,
P.
,
Kruer
,
M.C.
,
Gregory
,
A.
,
Wieland
,
T.
,
Schwarzmayr
,
T.
et al. 
(
2012
)
Exome sequencing reveals de novo WDR45 mutations causing a phenotypically distinct, X-linked dominant form of NBIA
.
Am. J. Hum. Genet.
91
,
1144
1149
doi:
24
Ebrahimi-Fakhari
,
D.
,
Saffari
,
A.
,
Wahlster
,
L.
,
Lu
,
J.
,
Byrne
,
S.
,
Hoffmann
,
G.F.
et al. 
(
2016
)
Congenital disorders of autophagy: an emerging novel class of inborn errors of neuro-metabolism
.
Brain
139
,
317
337
doi:
25
Park
,
J.-S.
,
Blair
,
N.F.
and
Sue
,
C.M.
(
2015
)
The role of ATP13A2 in Parkinson's disease: clinical phenotypes and molecular mechanisms
.
Mov. Disord.
30
,
770
779
doi:
26
Matsui
,
H.
,
Sato
,
F.
,
Sato
,
S.
,
Koike
,
M.
,
Taruno
,
Y.
,
Saiki
,
S.
et al. 
(
2013
)
ATP13A2 deficiency induces a decrease in cathepsin D activity, fingerprint-like inclusion body formation, and selective degeneration of dopaminergic neurons
.
FEBS Lett.
587
,
1316
1325
doi:
27
Bento
,
C.F.
,
Ashkenazi
,
A.
,
Jimenez-Sanchez
,
M.
and
Rubinsztein
,
D.C.
(
2016
)
The Parkinson's disease-associated genes ATP13A2 and SYT11 regulate autophagy via a common pathway
.
Nat. Commun
.
7
,
11803
doi:
28
Schapira
,
A.H.V.
(
2015
)
Glucocerebrosidase and Parkinson disease: recent advances
.
Mol. Cell. Neurosci.
66
,
37
42
doi:
29
Du
,
T.-T.
,
Wang
,
L.
,
Duan
,
C.-L.
,
Lu
,
L.-L.
,
Zhang
,
J.-L.
,
Gao
,
G.
et al. 
(
2015
)
GBA deficiency promotes SNCA/α-synuclein accumulation through autophagic inhibition by inactivated PPP2A
.
Autophagy
11
,
1803
1820
doi:
30
Magalhaes
,
J.
,
Gegg
,
M.E.
,
Migdalska-Richards
,
A.
,
Doherty
,
M.K.
,
Whitfield
,
P.D.
and
Schapira
,
A.H.
(
2016
)
Autophagic lysosome reformation dysfunction in glucocerebrosidase deficient cells: relevance to Parkinson disease
.
Hum. Mol. Genet.
first published online July 4 doi:
31
Burchell
,
V.S.
,
Nelson
,
D.E.
,
Sanchez-Martinez
,
A.
,
Delgado-Camprubi
,
M.
,
Ivatt
,
R.M.
,
Pogson
,
J.H.
et al. 
(
2013
)
The Parkinson's disease-linked proteins Fbxo7 and Parkin interact to mediate mitophagy
.
Nat. Neurosci.
16
,
1257
1265
doi:
32
Drouet
,
V.
and
Lesage
,
S.
(
2014
)
Synaptojanin 1 mutation in Parkinson's disease brings further insight into the neuropathological mechanisms
.
Biomed. Res. Int
.
2014
,
289728
PMID:
[PubMed]
33
George
,
A.A.
,
Hayden
,
S.
,
Stanton
,
G.R.
and
Brockerhoff
,
S.E.
(
2016
)
Arf6 and the 5' phosphatase of synaptojanin 1 regulate autophagy in cone photoreceptors
.
BioEssays
38
,
S119
S135
doi:
34
Gan-Or
,
Z.
,
Ozelius
,
L.
,
Bar-Shira
,
A.
,
Saunders-Pullman
,
R.
,
Mirelman
,
A.
,
Kornreich
,
R.
et al. 
(
2013
)
The p.L302P mutation in the lysosomal enzyme gene SMPD1 is a risk factor for Parkinson disease
.
Neurology
80
,
1606
1610
doi:
35
Kirkegaard
,
T.
,
Roth
,
A.G.
,
Petersen
,
N.H.T.
,
Mahalka
,
A.K.
,
Olsen
,
O.D.
,
Moilanen
,
I.
et al. 
(
2010
)
Hsp70 stabilizes lysosomes and reverts Niemann-Pick disease-associated lysosomal pathology
.
Nature
463
,
549
553
doi:
36
Perrotta
,
C.
,
Cervia
,
D.
,
De Palma
,
C.
,
Assi
,
E.
,
Pellegrino
,
P.
,
Bassi
,
M.T.
et al. 
(
2015
)
The emerging role of acid sphingomyelinase in autophagy
.
Apoptosis
20
,
635
644
doi:
37
Friedman
,
L.G.
,
Lachenmayer
,
M.L.
,
Wang
,
J.
,
He
,
L.
,
Poulose
,
S.M.
,
Komatsu
,
M.
et al. 
(
2012
)
Disrupted autophagy leads to dopaminergic axon and dendrite degeneration and promotes presynaptic accumulation of α-synuclein and LRRK2 in the brain
.
J. Neurosci.
32
,
7585
7593
doi:
38
Plowey
,
E.D.
,
Cherra
, III,
S.J.
,
Liu
,
Y.-J.
and
Chu
,
C.T.
(
2008
)
Role of autophagy in G2019S-LRRK2-associated neurite shortening in differentiated SH-SY5Y cells
.
J. Neurochem.
105
,
1048
1056
doi:
39
Alegre-Abarrategui
,
J.
,
Christian
,
H.
,
Lufino
,
M.M.
,
Mutihac
,
R.
,
Venda
,
L.L.
,
Ansorge
,
O.
et al. 
(
2009
)
LRRK2 regulates autophagic activity and localizes to specific membrane microdomains in a novel human genomic reporter cellular model
.
Hum. Mol. Genet.
18
,
4022
4034
doi:
40
Gómez-Suaga
,
P.
,
Luzón-Toro
,
B.
,
Churamani
,
D.
,
Zhang
,
L.
,
Bloor-Young
,
D.
,
Patel
,
S.
et al. 
(
2012
)
Leucine-rich repeat kinase 2 regulates autophagy through a calcium-dependent pathway involving NAADP
.
Hum. Mol. Genet.
21
,
511
525
doi:
41
Henry
,
A.G.
,
Aghamohammadzadeh
,
S.
,
Samaroo
,
H.
,
Chen
,
Y.
,
Mou
,
K.
,
Needle
,
E.
et al. 
(
2015
)
Pathogenic LRRK2 mutations, through increased kinase activity, produce enlarged lysosomes with reduced degradative capacity and increase ATP13A2 expression
.
Hum. Mol. Genet.
24
,
6013
6028
doi:
42
Manzoni
,
C.
,
Mamais
,
A.
,
Dihanich
,
S.
,
Abeti
,
R.
,
Soutar
,
M.P.
,
Plun-Favreau
,
H.
et al. 
(
2013
)
Inhibition of LRRK2 kinase activity stimulates macroautophagy
.
Biochim. Biophys. Acta Mol. Cell Res.
1833
,
2900
2910
doi:
43
Manzoni
,
C.
,
Mamais
,
A.
,
Roosen
,
D.A.
,
Dihanich
,
S.
,
Soutar
,
M.P.
,
Plun-Favreau
,
H.
et al. 
(
2016
)
mTOR independent regulation of macroautophagy by leucine rich repeat kinase 2 via Beclin-1
.
Sci. Rep
.
6
,
35106
doi:
44
Saez-Atienzar
,
S.
,
Bonet-Ponce
,
L.
,
Blesa
,
J.R.
,
Romero
,
F.J.
,
Murphy
,
M.P.
,
Jordan
,
J.
et al. 
(
2014
)
The LRRK2 inhibitor GSK2578215A induces protective autophagy in SH-SY5Y cells: involvement of Drp-1-mediated mitochondrial fission and mitochondrial-derived ROS signaling
.
Cell Death Dis.
5
,
e1368
doi:
45
Schapansky
,
J.
,
Nardozzi
,
J.D.
,
Felizia
,
F.
and
LaVoie
,
M.J.
(
2014
)
Membrane recruitment of endogenous LRRK2 precedes its potent regulation of autophagy
.
Hum. Mol. Genet.
23
,
4201
4214
doi:
46
Bang
,
Y.
,
Kim
,
K.-S.
,
Seol
,
W.
and
Choi
,
H.J.
(
2016
)
LRRK2 interferes with aggresome formation for autophagic clearance
.
Mol. Cell. Neurosci.
75
,
71
80
doi:
47
Bravo-San Pedro
,
J.M.
,
Niso-Santano
,
M.
,
Gómez-Sánchez
,
R.
,
Pizarro-Estrella
,
E.
,
Aiastui-Pujana
,
A.
,
Gorostidi
,
A.
et al. 
(
2013
)
The LRRK2 G2019S mutant exacerbates basal autophagy through activation of the MEK/ERK pathway
.
Cell. Mol. Life Sci.
70
,
121
136
doi:
48
Manzoni
,
C.
,
Mamais
,
A.
,
Dihanich
,
S.
,
McGoldrick
,
P.
,
Devine
,
M.J.
,
Zerle
,
J.
et al. 
(
2013
)
Pathogenic Parkinson's disease mutations across the functional domains of LRRK2 alter the autophagic/lysosomal response to starvation
.
Biochem. Biophys. Res. Commun.
441
,
862
866
doi:
49
Sánchez-Danés
,
A.
,
Richaud-Patin
,
Y.
,
Carballo-Carbajal
,
I.
,
Jiménez-Delgado
,
S.
,
Caig
,
C.
,
Mora
,
S.
et al. 
(
2012
)
Disease-specific phenotypes in dopamine neurons from human iPS-based models of genetic and sporadic Parkinson's disease
.
EMBO Mol. Med.
4
,
380
395
doi:
50
Tong
,
Y.
,
Giaime
,
E.
,
Yamaguchi
,
H.
,
Ichimura
,
T.
,
Liu
,
Y.
,
Si
,
H.
et al. 
(
2012
)
Loss of leucine-rich repeat kinase 2 causes age-dependent bi-phasic alterations of the autophagy pathway
.
Mol. Neurodegener
.
7
,
2
doi: .
51
Ramonet
,
D.
,
Daher
,
J.P.
,
Lin
,
B.M.
,
Stafa
,
K.
,
Kim
,
J.
,
Banerjee
,
R.
et al. 
(
2011
)
Dopaminergic neuronal loss, reduced neurite complexity and autophagic abnormalities in transgenic mice expressing G2019S mutant LRRK2
.
PLoS ONE
6
,
e18568
doi:
52
Orenstein
,
S.J.
,
Kuo
,
S.-H.
,
Tasset
,
I.
,
Arias
,
E.
,
Koga
,
H.
,
Fernandez-Carasa
,
I.
et al. 
(
2013
)
Interplay of LRRK2 with chaperone-mediated autophagy
.
Nat. Neurosci
.
16
,
394
406
doi:
53
Su
,
Y.-C.
,
Guo
,
X.
and
Qi
,
X.
(
2015
)
Threonine 56 phosphorylation of Bcl-2 is required for LRRK2 G2019S-induced mitochondrial depolarization and autophagy
.
Biochim. Biophys. Acta Mol. Basis Dis.
1852
,
12
21
doi:
54
Saez-Atienzar
,
S.
,
Bonet-Ponce
,
L.
,
da Casa
,
C.
,
Perez-Dolz
,
L.
,
Blesa
,
J.R.
,
Nava
,
E.
et al. 
(
2016
)
Bcl-xL-mediated antioxidant function abrogates the disruption of mitochondrial dynamics induced by LRRK2 inhibition
.
Biochim. Biophys. Acta Mol. Basis Dis.
1862
,
20
31
doi:
55
Soukup
,
S.F.
,
Kuenen
,
S.
,
Vanhauwaert
,
R.
,
Manetsberger
,
J.
,
Hernández-Díaz
,
S.
,
Swerts
,
J.
et al. 
(
2016
)
LRRK2-dependent endophilinA phosphoswitch is critical for macroautophagy at presynaptic terminals
.
Neuron
doi:
This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY).