Amyotrophic Lateral Sclerosis: Focus on Cytoplasmic Trafficking and Proteostasis

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal motor neuron disease characterized by the pathological loss of upper and lower motor neurons. Whereas most ALS cases are caused by a combination of environmental factors and genetic susceptibility, in a relatively small proportion of cases, the disorder results from mutations in genes that are inherited. Defects in several different cellular mechanisms and processes contribute to the selective loss of motor neurons (MNs) in ALS. Prominent among these is the accumulation of aggregates of misfolded proteins or peptides which are toxic to motor neurons. These accumulating aggregates stress the ability of the endoplasmic reticulum (ER) to function normally, cause defects in the transport of proteins between the ER and Golgi, and impair the transport of RNA, proteins, and organelles, such as mitochondria, within axons and dendrites, all of which contribute to the degeneration of MNs. Although dysfunction of a variety of cellular processes combines towards the pathogenesis of ALS, in this review, we focus on recent advances concerning the involvement of defective ER stress, vesicular transport between the ER and Golgi, and axonal transport.

Keywords: Amyotrophic lateral sclerosis; Axonal transport; Endoplasmic reticulum stress; Neurodegenerative diseases; Unfolded protein response; Vesicular transport.

Fig. 1

Multiple cellular processes impacted by the accumulation of protein and RNA aggregates. Accumulation of protein aggregates impairs several cellular processes including autophagy and proteasomal degradation, mitochondrial function, nucleocytoplasmic transport, and axonal transport. Additionally, protein and RNA foci in the nucleus affect nuclear function. Impaired vesicular transport between the ER and Golgi causes Golgi dysfunction and fragmentation

Fig. 2

C9orf72 mutation has both loss-of-function and gain-of-function effects. Among the loss-of-function effects is reduced transcription, which leads to reduced production of functional C9orf72 protein. Gain-of-function mutations result from the production of RNA fragments that aggregate in RNA foci impairing nuclear function and the production of DPRs which aggregate in the cytoplasm impairing multiple processes including vesicular transport, axonal transport, and mitochondrial function

Fig. 3

Transport between the ER and Golgi. A Luminal and membrane proteins from the ER are transported in COP-II vesicles which bud off from regions of the smooth ER called ERES. Most of the vesicles move the ERGIC before budding off from it and fusing to the cis-Golgi membrane. Some secretory proteins are transported in COPII-coated vesicles directly to the Golgi via microtubules. Membrane and soluble proteins are transported from the Golgi to the ER, including ER-resident proteins, that are transported in COPI-coated vesicles. B The vesical formation, COPII coating, and exit from the ER are initiated by the recruitment of the Sar1-GTPase to the ER membrane and activation of Sar1-GDP to Sar1-GTP by the SAR1-GEF, Sec16. C The vesical formation, COPI coating, and exit from the cis-Golgi are initiated by the recruitment of the Arf1-GTPase to the Golgi membrane and activation of Arf1-GDP to Arf1-GTP by the Arf-GEF

Fig. 4

The UPR signalling pathways. When the ER is functioning under normal conditions, the UPR composed of the IRE-1a, PERK, and ATF6 is inhibited by the binding of BiP. Under conditions of ER stress, BiP disassociates activating the catalytic activities of IRE1α and PERK and permitting the translocation of ATF6 to the Golgi apparatus, where it is cleaved to generate active ATF6. Together, these proteins upregulate the production of chaperones, strengthen ERAD, and upregulate lipid synthesis for expansion of the ER membrane. If the stress cannot be resolved, the IRE1α and PERK pathways activate apoptosis-promoting molecules, including JNK and ATF4 (which now stimulate the transcription of pro-apoptotic genes). Figure modified from Lukas et al. Adv. Med. Sciences (2019)