Pathological changes in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

Abstract

Amyotrophic lateral sclerosis (ALS) and Frontotemporal Lobular Degeneration (FTLD) are two devastating neurodegenerative diseases with a shared pathological hallmark of the abnormal aggregation of transactive response DNA binding (TDP-43) protein, which is a member of the heterogenous nuclear ribonucleoprotein (hnRNP) family.

Expanding on a recent study that found diffuse non-ubiqutinated TDP-43 inclusions are more common in patients with rapid disease, Chapter 2 quantifies the severity of inclusions of TDP-43 and autophagy protein p62 in the upper and lower motor neurons of 31 patients with sporadic ALS with short (<2 years) compared to longer (4-7 years) disease durations. This study demonstrated significantly more TDP-43 and p62 aggregates in the motor neurons of the spinal cord anterior horn in patients with a short compared to longer disease duration, with the severity of p62 inclusions demonstrating a negative association with survival. This suggests survival in ALS is associated with the clearance of TDP-43/p62 aggregates from motor neurons of the spinal cord and that defective autophagy pathways may underpin the higher density of TDP-43 aggregates observed in patients with more rapid disease.

Given that recent evidence implicates hnRNPs other than TDP-43 in FTLD and ALS, Chapter 3 assesses seven hnRNPs which had not previously been comparatively assessed in the frontal and motor cortices of FTLD and ALS patients (hnRNP A1, A2B1, A0, C, DL, AB, H2). We observed a significant loss of normal neuronal nuclear hnRNP A1, hnRNP C and hnRNP DL hnRNP AB, in the frontal cortex FTLD patients. The loss of normal hnRNP A1 and hnRNP C was accompanied by their localisation in the cytoplasm, which rarely co-localised with TDP-43. HnRNP AB and hnRNP DL, which are members of the hnRNP D sub-family, demonstrated a negative association with TDP-43 cytoplasmic inclusions. This implicates hnRNP D, C and A1 in sporadic FTLD, highlighting the need for further exploration.