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.