Tissue-selective regulation of protein homeostasis and unfolded protein response signalling in sporadic ALS.

Amyotrophic lateral sclerosis (ALS) is a disorder that affects motor neurons in motor cortex and spinal cord, and the degeneration of both neuronal populations is a critical feature of the disease. Abnormalities in protein homeostasis (proteostasis) are well established in ALS. However, they have been investigated mostly in spinal cord but less so in motor cortex. Herein, we monitored the unfolded protein (UPR) and heat shock response (HSR), two major proteostasis regulatory pathways, in human post-mortem tissue derived from the motor cortex of sporadic ALS (SALS) and compared them to those occurring in spinal cord. Although the UPR was activated in both tissues, specific expression of select UPR target genes, such as PDIs, was observed in motor cortex of SALS cases strongly correlating with oligodendrocyte markers. Moreover, we found that endoplasmic reticulum-associated degradation (ERAD) and HSR genes, which were activated predominately in spinal cord, correlated with the expression of neuronal markers. Our results indicate that proteostasis is strongly and selectively activated in SALS motor cortex and spinal cord where subsets of these genes are associated with specific cell type. This study expands our understanding of convergent molecular mechanisms occurring in motor cortex and spinal cord and highlights cell type-specific contributions.

Patient-Derived Induced Pluripotent Stem Cells and Organoids for Modeling Alpha Synuclein Propagation in Parkinson's Disease.

Parkinson's disease (PD) is an age-associated, progressive neurodegenerative disorder characterized by motor impairment and in some cases cognitive decline. Central to the disease pathogenesis of PD is a small, presynaptic neuronal protein known as alpha synuclein (a-syn), which tends to accumulate and aggregate in PD brains as Lewy bodies or Lewy neurites. Numerous in vitro and in vivo studies confirm that a-syn aggregates can be propagated from diseased to healthy cells, and it has been suggested that preventing the spread of pathogenic a-syn species can slow PD progression. In this review, we summarize the works of recent literature elucidating mechanisms of a-syn propagation, and discussed the advantages in using patient-derived induced pluripotent stem cells (iPSCs) and/or induced neurons to study a-syn transmission.

Cell cycle inhibitors protect motor neurons in an organoid model of Spinal Muscular Atrophy.

Spinal Muscular Atrophy (SMA) is caused by genetic mutations in the SMN1 gene, resulting in drastically reduced levels of Survival of Motor Neuron (SMN) protein. Although SMN is ubiquitously expressed, spinal motor neurons are one of the most affected cell types. Previous studies have identified pathways uniquely activated in SMA motor neurons, including a hyperactivated ER stress pathway, neuronal hyperexcitability, and defective spliceosomes. To investigate why motor neurons are more affected than other neural types, we developed a spinal organoid model of SMA. We demonstrate overt motor neuron degeneration in SMA spinal organoids, and this degeneration can be prevented using a small molecule inhibitor of CDK4/6, indicating that spinal organoids are an ideal platform for therapeutic discovery.