CMT2B (Charcot–Marie–Tooth type 2B) disease is an autosomal dominant peripheral neuropathy whose onset is in the second or third decade of life, thus in adolescence or young adulthood. CMT2B is clinically characterized by severe symmetric distal sensory loss, reduced tendon reflexes at ankles, weakness in the lower limbs and muscle atrophy, complicated by ulcerations that often lead to amputations. Four missense mutations in the gene encoding the small GTPase Rab7 cause the CMT2B neuropathy. Rab7 is a ubiquitous protein that regulates transport to late endosomes and lysosomes in the endocytic pathway. In neurons, Rab7 is important for endosomal trafficking and signalling of neurotrophins, and for retrograde axonal transport. Recent data on CMT2B-causing Rab7 mutant proteins show that these proteins exhibit altered koff rates and, as a consequence, they are mainly in the GTP-bound state and bind more strongly to Rab7 effector proteins. Notably, expression of CMT2B-causing Rab7 mutant proteins strongly inhibit neurite outgrowth in several cells lines and alter NGF (nerve growth factor) trafficking and signalling. These data indicate that Rab7 plays an essential role in neuronal cells and that CMT2B-causing Rab7 mutant proteins alter neuronal specific pathways, but do not fully explain why only peripheral neurons are affected in CMT2B. In the present paper, we discuss the current understanding of the molecular and cellular mechanisms underlying CMT2B, and we consider possible hypotheses in order to explain how alterations of Rab7 function lead to CMT2B.

Introduction

CMT2B (Charcot–Marie–Tooth type 2B) disease is a peripheral neuropathy characterized by prominent sensory loss and normal or near-normal nerve conduction velocities [13]. The disease onset is in the second or third decade of life and typical features are weakness in the foot and lower leg muscles, muscle atrophy and foot deformities [4]. CMT2B disease is an ulcero-mutilating neuropathy, as patients show frequent ulcers and recurrent infections, often leading to amputations of the toes. CMT2B is an axonal autosomal dominant form of the CMT disease caused by mutations in the RAB7 gene [57].

The family of Rab GTPases comprises approximately 70 small G-proteins in humans that finely control several different aspects of intracellular trafficking, being involved in vesicle budding, moving, tethering and fusion [8]. The role of Rab proteins in membrane traffic and their involvement in signal transduction are fundamental for a broad range of physiological processes and thus Rab proteins are important for growth and differentiation [9]. Indeed, it has been demonstrated that Rab dysfunctions lead to several kind of genetic or acquired diseases [10].

The small GTPase Rab7 is localized on late endosomes and it regulates late endocytic trafficking [1113]. It is usually referred to as Rab7, but since a novel discovered Rab protein was called Rab7b, it has also been called Rab7a. Rab7 and Rab7b share high homology and partially co-localize at the level of late endosomes and lysosomes, although they have different functions. Indeed, whereas Rab7 regulates transport from early endosomes to late endosomes and lysosomes, Rab7b regulates transport from endosomes to the trans-Golgi network [1417].

Biochemical and functional characterization of CMT2B-causing Rab7 mutant proteins has been investigated in the last few years. These mutant proteins exhibit increased koff rates for nucleotides and thus they are able to release nucleotides more easily than the wild-type protein [1820]. The koff rate is particularly high for GDP, indicating a preference of these proteins in retaining GTP. As a consequence of increased koff rates for nucleotides, GTPase activity per binding event is impaired, although these mutant proteins do not exhibit a direct defect in the catalytic activity. These mutant proteins are mainly in the GTP-bound active form in cells and bind stronger than several wild-type effector proteins [18,19].

Despite these data, exactly how mutation in the RAB7 gene, encoding a ubiquitous protein, leads to a peripheral neuropathy is still unknown. Importantly, neuronal cells are often more sensitive to the altered functions of mutated proteins due to their specific morphology and functions. Indeed, defects in ubiquitous cell components often affect the nervous system. Rab7 has multiple roles in mammalian cells (Figure 1) and therefore several hypotheses can be proposed to explain how mutated Rab7 proteins cause a peripheral neuropathy. Clearly, it is important to consider not only neuronal specific processes controlled by Rab7, but also processes common to many cell types that are of particular importance to neurons and especially to peripheral neurons.

Multiple roles for the small GTPase Rab7

Figure 1
Multiple roles for the small GTPase Rab7

Rab7 regulates several cellular processes and, in neuronal cells, it controls specific functions such as neuronal migration, neurite outgrowth and neurotrophin signalling.

Figure 1
Multiple roles for the small GTPase Rab7

Rab7 regulates several cellular processes and, in neuronal cells, it controls specific functions such as neuronal migration, neurite outgrowth and neurotrophin signalling.

Rab7 and the nervous system

Rab7 regulates several neuronal-specific processes (Figure 1), and several studies associate alterations of Rab7 expression and/or activity with neurodegenerative diseases. As an example, significant up-regulation of RAB5 and RAB7 has been observed in hippocampal pyramidal neurons harvested from people who died from mild cognitive impairment and AD (Alzheimer's disease) [21].

We have demonstrated previously that Rab7 controls retrograde axonal transport of neurotrophin receptors TrkA and TrkB (tropomyosin receptor kinase A and B), thus regulating neurotrophin trafficking and signalling [22,23]. The activation of neurotrophin receptors such as TrkA, after binding of NGF (nerve growth factor), promotes neuronal survival, neurite outgrowth and long-distance axonal regeneration [24]. Signalling endosomes containing NGF and activated TrkA are transported retrogradely, from the axon tip to the cell body, by a Rab7-dependent mechanism [22]. Motor and sensory neurons, affected in CMT2B disease, have extremely long axons, thus it is reasonable to think that a small impairment in the transport to perinuclear regions of the cells will strongly influence transport over metres in neurons, whereas it will have little or no effect on other cell types. Mutations in Rab7 lead to altered neurotrophin traffic and impaired translocation of activated ERK1/2 (extracellular-signal-regulated kinase 1/2) [22,23,25]. However, expression of disease-causing mutant Rab7 proteins inhibits neurite outgrowth in several different cell lines also independently of NGF stimulation, indicating that other alternative Trk-independent pathways are also affected by these mutant proteins [26,27].

Interestingly, it has been reported that Rab7 regulates different steps of neuronal migration and maturation [28]. Cell migration is instrumental for injury-induced neurogenesis and tissue regeneration [29]. Although neuronal regeneration has not been demonstrated for the peripheral nervous system, one can hypothesize that dysregulation of neuronal migration could impair axonal regeneration and/or induce neurodegeneration in peripheral neurons.

Rab7 and autophagy

Autophagy is involved in a wide range of physiological and pathological processes, as responses to nutrient deprivation, development, tumour suppression, aging, cell death, survival and immunity [30]. It begins with the formation of a phagophore membrane that elongates and then closes forming a double-membraned vacuole called an autophagosome. The outer membrane can subsequently fuse with endosomes, to generate the amphisome that, after fusion with lysosomes, matures into an autolysosome. The autolysosomal content, together with the inner membrane, is digested by acidic hydrolases [31] (Figure 2).

Altered autophagy process in neurodegenerative diseases

Figure 2
Altered autophagy process in neurodegenerative diseases

The autophagosome is formed from a phagophore membrane that elongates and then closes to form a double-membraned vacuole. The amphisome and the autolysosomes are formed after fusion with endosomes and lysosomes respectively. The autolysosomal content, together with its inner membrane, is digested by acidic hydrolases. Lipidated LC3 (light chain 3) II protein is tightly associated with autophagosomes, whereas Rab7 is required for the normal progression of the autophagic pathway. FTLD and AD impair fusion of autophagosomes with endosomes and lysosomes, whereas HD and PD induce autophagy, promoting an autophagic process of cell death.

Figure 2
Altered autophagy process in neurodegenerative diseases

The autophagosome is formed from a phagophore membrane that elongates and then closes to form a double-membraned vacuole. The amphisome and the autolysosomes are formed after fusion with endosomes and lysosomes respectively. The autolysosomal content, together with its inner membrane, is digested by acidic hydrolases. Lipidated LC3 (light chain 3) II protein is tightly associated with autophagosomes, whereas Rab7 is required for the normal progression of the autophagic pathway. FTLD and AD impair fusion of autophagosomes with endosomes and lysosomes, whereas HD and PD induce autophagy, promoting an autophagic process of cell death.

Autophagy is the only known mechanism that eukaryotic cells possess to degrade protein aggregates and damaged organelles that cannot be processed by the proteasome, and dysregulation of autophagy results in the accumulation of abnormal proteins and/or damaged organelles, which is commonly observed in neurodegenerative diseases [32]. Neurodegeneration can be induced by both a lack and an excess of autophagy, indicating how crucial is the correct regulation of this process for neurons [33]. Abnormal accumulation of autophagic vacuoles is present in affected neurons in several neurodegenerative diseases and it promotes neuronal cell death by blocking the neuroprotective effects of autophagy against apoptosis and accumulation of toxic proteins [32].

Several neurodegenerative diseases are caused by loss of basal autophagy or imbalance of autophagic flux. For instance, in FTLD (frontotemporal lobar degeneration) accumulation of autophagosomes due to impaired fusion with endosomes and/or lysosomes has been reported [34]. In AD, autophagy is both induced and impaired, and autophagosomes accumulate in dystrophic neurites even though lysosomes are abundant, indicating that maturation of autophagosomes is impaired [35]. In PD (Parkinson's disease), α-synuclein, whose mutations cause familiar PD, leads to an increase in autophagy that has been associated with cell death [36]. In HD (Huntington's disease), mutant huntingtin aggregates in the nucleus and in the cytoplasm of affected neurons, and increased autophagy with an excess of autophagosomal structures has been reported in brains from HD patients [36].

A number of Rab GTPases have been shown to play either critical or accessory roles in autophagosomal biogenesis and maturation [37]. In particular, recruitment of Rab7 to autophagosomes is essential for fusion with endosomes and lysosomes [38,39]. In cultured Purkinje neurons, the rate of fusion between autophagosome and lysosome is regulated by a neurotrophic factor, IGF-I (insulin-like growth factor 1) that prevents deactivation of Rab7 and increases interaction of Rab7 with its effector RILP (Rab-interacting lysosomal protein), possibly facilitating the retrograde transport of autophagosomes [40].

Furthermore, a broad range of neurodegenerative disorders is characterized by neuronal damage caused by toxic aggregation of mutated proteins [41]. Recent studies showed Rab7 interaction with neurotoxic proteins. Indeed, Rab7 can interact with CLN3 (ceroid lipofuscinosis, neuronal 3), a lysosomal transmembrane protein, mutated in classical juvenile onset neuronal ceroid lipofuscinosis, a fatal inherited neurodegenerative lysosomal storage disorder, and with PrPc (cellular prion protein), mutated in prion disease [42,43]. Importantly, silencing of Rab7 induced considerable change in PrPc expression and localization in the neuronal cells [43].

All of these data strongly suggest that Rab7 activity is crucial for neuronal cell vitality possibly because of the role of Rab7 in modulating autophagy and regulating neurotoxic specific proteins, thus preventing neurodegeneration and/or stimulating axonal regeneration. Clearly, the role of autophagy in the CMT2B cell line model system should be investigated as it could help to elucidate the molecular mechanism underlying this neuropathy.

Rab7 and endocytosis

The main function of Rab7, however, remains the regulation of transport to late endocytic compartments, with Rab7 being important for correct transport of several ligands and receptors along the endocytic route [14]. It seems hard to imagine that dysregulation of this pathway will cause alterations only in peripheral neurons, as it is present in all cell types. However, the selective effect of the Rab7 mutants on neurons could be due to altered transport of a specific neuronal receptor (for instance, neurotrophin receptors) or of a receptor common to other cell types, but particularly important for neurons. As an example, Rab7 regulates transport of LDL (low-density lipoprotein) receptors [12]. Neurons are heavily dependent on endocytosed lipoprotein-associated cholesterol, which in turn affect neurotrophin signalling and neurite outgrowth [44]. Thus small alterations of LDL receptor trafficking could affect, in particular, neurons compared with other cell types.

How to control Rab7 activity?

The four CMT2B-causing mutants are mainly in the GTP-bound state in living mammalian cells and bind stronger to several Rab7 effectors, suggesting that increased activation of Rab7 causes the disease [18,19]. These data indicate that a target therapy for CMT2B could be based on lowering Rab7 activity.

Recently, several small molecules have been developed to modulate the activity of specific GTPases. These compounds specifically modulate the GTPase function by either targeting protein–protein interactions, and thus disrupting interaction of the G-protein with its effectors, or inhibiting GTP binding and/or membrane delivery. For instance, several inhibitors of the small oncogenic G-protein Ras have been identified as DCA1, which binds to Ras and blocks the SOS (Son of sevenless)-mediated nucleotide exchange, or salirasib [FTS (trans-farnesylthiosalicylic acid)] which competes with Ras-GTP for binding to a specific saturable binding site in the plasma membrane, preventing active Ras from interacting with its prominent downstream effectors and resulting in reversal of the transformed phenotype in cells that harbour activated Ras [45,46]. NSC23766 and EHT1864 are specific inhibitors of Rac1: NSC23766 blocks specifically the interaction between Rac1 and a Rac-specific GEF (guanine-nucleotide-exchange factor) acting as a Rac1 activation inhibitor, whereas EHT1864 inhibits Rac1 signalling and APP (amyloid precursor protein) processing, lowering β-amyloid peptide production in vitro and leading to a decrease in β-amyloid peptide in the brain of guinea pigs, thus representing a possible treatment for AD [47].

For Rab proteins, as prenylation is responsible for membrane delivery and it is mediated by a RabGGTase (Rab geranylgeranyltransferase) which covalently attaches two (or, in a few cases, one) geranylgeranyl moieties to cysteine residues at their C-terminus, inhibitors of RabGGTase have been used [48,49].

Using HTS (high-throughput screening), the first competitive Rab7 GTPase inhibitor, CID 1067700, has been identified [50]. CID 1067700 fills the nucleotide-binding pocket of GTP, but exhibits inhibitory activity on other small GTPases [50]. The identification of CID 1067700, together with the analysis of its structure–activity relationship, suggests that it will be possible in the future to design selective inhibitors of Rab7. To modulate Rab7 activity directly or indirectly, a compound should block the interaction of Rab7 with specific downstream effectors, prevent protein prenylation and/or inhibit nucleotide (in particular GTP) binding. Ideally, for CMT2B, it would be very useful to develop a compound that would modulate selectively the activity of the disease-causing Rab7 mutant proteins and not of the wild-type.

Future perspectives

As discussed above, given the multiple functions of the small GTPase Rab7, there are several possible hypotheses that could explain why mutations in a ubiquitous protein cause a peripheral neuropathy such as CMT2B. Further investigation of the effect of Rab7 mutant proteins on autophagy, neurite outgrowth, neurotrophin signalling, cholesterol transport, neuronal degeneration and axonal regeneration in proper cell types as primary peripheral motor and sensory neurons will surely help us to find answers. In addition, it will be extremely important to generate animal models of the disease and to start working on patient cells, when available, to validate and extend the data already obtained in cell lines and in order to establish the precise molecular mechanisms underlying CMT2B. Clearly, in order to find effective treatments for CMT2B, it would be of importance to identify compounds that will selectively lower the activity of the disease-causing Rab7 mutant proteins.

Rab GTPases and Their Interacting Proteins in Health and Disease: A Biochemical Society Focused Meeting held at University College Cork, Cork, Ireland, 11–13 June 2012. Organized and Edited by Mary McCaffrey (University College Cork, Ireland).

Abbreviations

     
  • AD

    Alzheimer’s disease

  •  
  • CMT2B

    Charcot–Marie–Tooth type 2B

  •  
  • FTLD

    frontotemporal lobar degeneration

  •  
  • HD

    Huntington’s disease

  •  
  • LDL

    low-density lipoprotein

  •  
  • NGF

    nerve growth factor

  •  
  • PD

    Parkinson’s disease

  •  
  • PrPc

    cellular prion protein

  •  
  • RabGGTase

    Rab geranylgeranyltransferase

  •  
  • Trk

    tropomyosin receptor kinase

We thank Pietro Alifano for a critical reading of the paper before submission.

Funding

Work in our laboratory was supported by Telethon-Italy [grant number GGP09045 (to C.B.)] and the Associazione Italiana per la Ricerca sul Cancro (AIRC) [Investigator Grant number 10213 (to C.B.)]. M.D.L. is supported by a Fondazione Italiana Ricerca Cancro (FIRC) Fellowship.

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