Protein homeostasis regulation in amyotrophic lateral sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a disorder that affects motor neurons in the motor cortex, brainstem and spinal cord. The lack of an effective treatment indicates the need for a deeper understanding of the pathogenesis underlying this disease. ALS, as well as the majority of neurodegenerative diseases such as Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD) are characterised by dysfunctions in protein homeostasis (proteostasis). The endoplasmic reticulum (ER) plays an important role in proteostasis through the unfolded protein response (UPR). We therefore started this thesis by characterising the UPR signalling pathways in human post-mortem spinal cord from sporadic ALS (SALS) and in frontal and temporal cortex from FTLD and AD cases and compared with healthy controls. In ALS, UPR activation was confirmed by a substantial expression increase of both known and novel target genes involved particularly in ER-associated degradation (ERAD), while in AD a distinct pattern emerged, with a predominant involvement of protein folding genes, such as Protein Disulphide Isomerases (PDIs). Similarly, in human motor cortex of SALS cases we found an increased expression of PDIs and other specific UPR target genes which correlated with oligodendrocyte markers. Moreover, we found that the heat shock response (HSR), a major proteostasis regulatory pathway, and ERAD genes were activated predominately in the spinal cord and strongly correlated with the motor neuron marker VAPB. Finally, we performed a meta-analysis of publicly available RNA-Seq studies derived from the spinal cord of healthy and ALS cases. We identified cholesterol metabolism, cell adhesion and regulation of vesicle-mediated transport as top disease-associated processes and 21 hub genes as central nodes in these networks. We conclude that proteostasis is strongly and selectively activated specific cell types in SALS motor cortex and spinal cord. Hence, these results provide novel insights into the pathophysiology of ALS and other neurodegenerative disorders.