Emerging nexus between RAB GTPases, autophagy and neurodegeneration

Figures & data

Figure 1. Core autophagic machinery and its regulation by RAB proteins. Schematic diagram showing the role of the core autophagic machinery and its regulation by RAB proteins. 1. Induction: The initial phagophore assembly site (PAS) could be contributed to by any of the multiple organelles, each requiring a set of proteins regulated by RAB activity. The signal is most often under the control of ULK1, the activity of which can also be regulated by RAB accessory proteins. 2. Nucleation: At the PAS, binds the initial set of proteins that help in membrane elongation/expansion, mediated by activated lipid (PtdIns3P), to which bind proteins such as PIK3C3/VPS34, that is a direct effector of activated RAB5. 3. Elongation: The ubiquitin-like conjugation machinery of ATG12–ATG5–ATG16L1 is also under the control of an ER resident RAB, RAB33B. 4. Completion: The fusion of the final double-layered autophagosome with the acidic lysosome for degradation of cargo is also under the control of activity of the late endosome-specific RAB7A and RAB24. Protein names in star-shaped boxes represent the proteins that are directly regulated by the respective RAB proteins.

Table 1. List of neurodegenerative disorders with abnormal activities for RAB GTPase.

Alzheimer disease (AD) and mild	RAB4A: Required for mitochondrial autophagy.^14
	RAB5A: Regulates activity of PIK3C3-BECN1 complex.^14
cognitive impairment (MCI)	RAB7A: Required for autophagosome-lysosome fusion.^14
	RAB27A: Transcripts were upregulated in brains of AD and MCI patients.^14
	RAB4 and RAB6A are upregulated in the triple-transgenic mouse model of AD.^33
Amyotrophic lateral sclerosis (ALS)	RAB1A: Involved in endoplasmic reticulum-mediated autophagosome formation, and accumulated as inclusions in neurons of sporadic ALS patients.^31
	RAB1A: Overexpression rescued inclusion formation in mouse model of ALS.^32
Charcot-Marie-Tooth type 2B (CMT2B)	RAB7A: Mutations resulting in its enhanced activity are a causative factor for familial CMT2B.^11
Dementia with Lewy bodies (DLB)	RAB7A: Levels are increased in brains of patients with DLB.^17
Huntington disease (HD)	RAB11A: Involved in recycling endosome-mediated autophagosome formation, interacts with HTT and is inactive in knock-in mouse model of HD.^34
Lafora disease (LD)	RAB5A: Required for autophagosome formation, is upregulated in mouse model of LD.^16

Note. MCI, mild cognitive impairment.

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