TDP-43 Cryptic RNAs in Perry Syndrome: Differences across Brain Regions and TDP-43 Proteinopathies.

Background: Perry syndrome (PS) is a rare and fatal hereditary autosomal dominant neurodegenerative disorder caused by mutations in dynactin (DCTN1). PS brains accumulate inclusions positive for ubiquitin, transactive-response DNA-binding protein of 43 kDa (TDP-43), and to a lesser extent dynactin.

Objectives: Little is known regarding the contributions of TDP-43, an RNA binding protein that represses cryptic exon inclusion, in PS.

TNF receptor-associated factor 6 interacts with ALS-linked misfolded superoxide dismutase 1 and promotes aggregation.

Amyotrophic lateral sclerosis (ALS) is a fatal disease, characterized by the selective loss of motor neurons leading to paralysis. Mutations in the gene encoding superoxide dismutase 1 (SOD1) are the second most common cause of familial ALS, and considerable evidence suggests that these mutations result in an increase in toxicity due to protein misfolding. We previously demonstrated in the SOD1 rat model that misfolded SOD1 exists as distinct conformers and forms deposits on mitochondrial subpopulations.

Heterochromatin anomalies and double-stranded RNA accumulation underlie poly(PR) toxicity.

How hexanucleotide GGGGCC (GC) repeat expansions in cause frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) is not understood. We developed a mouse model engineered to express poly(PR), a proline-arginine (PR) dipeptide repeat protein synthesized from expanded GC repeats. The expression of green fluorescent protein-conjugated (PR) (a 50-repeat PR protein) throughout the mouse brain yielded progressive brain atrophy, neuron loss, loss of poly(PR)-positive cells, and gliosis, culminating in motor and memory impairments.

Poly(GR) impairs protein translation and stress granule dynamics in C9orf72-associated frontotemporal dementia and amyotrophic lateral sclerosis.

The major genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) is a C9orf72 GC repeat expansion. Proposed mechanisms by which the expansion causes c9FTD/ALS include toxicity from repeat-containing RNA and from dipeptide repeat proteins translated from these transcripts. To investigate the contribution of poly(GR) dipeptide repeat proteins to c9FTD/ALS pathogenesis in a mammalian in vivo model, we generated mice that expressed GFP-(GR) in the brain.