Absence of alsin function leads to corticospinal motor neuron vulnerability via novel disease mechanisms

Abstract

Mutations in the ALS2 gene result in early-onset amyotrophic lateral sclerosis, infantile-onset ascending hereditary spastic paraplegia and juvenile primary lateral sclerosis, suggesting prominent upper motor neuron involvement. However, the importance of alsin function for corticospinal motor neuron (CSMN) health and stability remains unknown. To date, four separate alsin knockout (AlsinKO) mouse models have been generated, and despite hopes of mimicking human pathology, none displayed profound motor function defects. This, however, does not rule out the possibility of neuronal defects within CSMN, which is not easy to detect in these mice. Detailed cellular analysis of CSMN has been hampered due to their limited numbers and the complex and heterogeneous structure of the cerebral cortex. In an effort to visualize CSMN in vivo and to investigate precise aspects of neuronal abnormalities in the absence of alsin function, we generated AlsinKO-UeGFP mice, by crossing AlsinKO and UCHL1-eGFP mice, a CSMN reporter line. We find that CSMN display vacuolated apical dendrites with increased autophagy, shrinkage of soma size and axonal pathology even in the pons region. Immunocytochemistry coupled with electron microscopy reveal that alsin is important for maintaining cellular cytoarchitecture and integrity of cellular organelles. In its absence, CSMN displays selective defects both in mitochondria and Golgi apparatus. UCHL1-eGFP mice help understand the underlying cellular factors that lead to CSMN vulnerability in diseases, and our findings reveal unique importance of alsin function for CSMN health and stability.

Mitochondria, ER, and nuclear membrane defects reveal early mechanisms for upper motor neuron vulnerability with respect to TDP-43 pathology

“…4i), by crossing prp-TDP-43 A315T with UCHL1-eGFP mice, a well-characterized reporter line of CSMN [76]. This reporter line was previously used to reveal details of CSMN in hSOD1G93A [76] and AlsinKO mice [21]. …”

“…Thus, their contribution to disease progression has been widely questioned and they have not been acknowledged as a potential cellular target for therapeutic interventions. Only recently, numerous independent studies have begun to highlight early signs of their degeneration and dysfunction in ALS patients [22, 23, 69] and in different mouse models of the disease [21, 33, 47], revealing their early cellular degeneration and direct involvement in disease pathology. Therefore, understanding the underlying causes of their vulnerability and progressive degeneration is paramount and extremely relevant for building effective treatment strategies.…”

Rab5 and Alsin regulate stress-activated cytoprotective signaling on mitochondria

“…However, these mouse 368 lines failed to recapitulate the phenotypes observed in human patients (Cai, Shim et al, 2008). It has 369 recently been reported that absence of Alsin appear to specifically affect the health of corticospinal 370 motor neurons (Gautam et al, 2016). Therefore, in order to directly probe for the role of Alsin in a 371 more physiological background without compromising our ability for genetic and chemical 372 manipulations, we decided to generate Alsin CRISPR knockout cells in human induced pluripotent 373 stem cells (iPSCs).…”

Multi-Omic Analyses of Growth Cones at Different Developmental Stages Provides Insight into Pathways in Adult Neuroregeneration

“…Alsin or Als2 signaling is necessary for control of axonal growth (Jacquier et al, 2006). Conversely, Als2 deficiency results in axonal growth defects (Gautam et al, 2016;Otomo et al, 2008) and distal axonopathy (Deng et al, 2007). The GO biological processes, based on homology implicated Als2 and Hmgcs1 (cytoplasmic hydroxymethylglutaryl-CoA synthase) in axonogenesis.…”