Table 2.

ALS genes with roles in vesicular transport and EV regulation. Abbreviations: DPR—dipeptide repeat proteins, RBP—RNA binding proteins, UPS—ubiquitin proteasome system, NF-κB—nuclear factor kappa B.

Gene	Proteins	Molecular Pathways Affected
C9orf72 [59,68]	C9orf72 short and long isoforms	Loss of function in vesicle trafficking, autophagy and endo-lysosomal pathway Gain of toxicity with development of RNA foci and DPR
VAPB [62,63]	Vesicle-associated membrane protein-associated protein B/C	Aggregation of VAPB protein, altered autophagy and vesicular transport, accumulation of RBPs
FIG4 [60]	Polyphosphoinositide phosphatase	Loss of function in trafficking of endosomal vesicles to golgi and autophagy regulation
ALS2 [61]	Alsin	Alteration of Rab5-mediated pathway with dysregulation of endosomal trafficking Altered trafficking of AMPA receptors causing glutamate toxicity
CHMP2B [58]	Charged multivesicular body protein 2b	Dysfunction of autophagy and endo-lysosomal pathway, resulting in accumulation of enlarged endosomes and autophagic organelles
SPG11 [64]	Spatacsin	Impaired autophagy, lipid sorting in late endosomes and lysosomal dysfunction with lipid accumulation
SQSTM1 [69]	Sequestosome-1/p62	Dysfunction of autophagy and protein degradation through UPS
OPTN [70]	Optineurin	Golgi fragmentation, impaired autophagy and vesicular transport Loss of inhibitory action on NF-κB leading to abnormal inflammatory response
UBQLN2 [71]	Ubiquilin 2	Impaired protein degradation via UPS and dysfunction of autophagy and endo-lysosomal pathway
VCP [72,73]	Valosin Containing Protein	Impaired protein degradation via UPS and dysfunction of autophagy and endo-lysosomal pathway
TBK1 [74]	Tank Binding Kinase 1	Dysregulation of multiple autophagy pathways