Pathogenic Mechanisms of ALS and Motor Neuron Diseases

National Institute On Aging

Investigators

Linked publications, trials & patents

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease marked by progressive degeneration of motor neurons, including corticospinal motor neurons (CSMNs), leading to severe motor impairment. A missense mutation in vesicle-associated membrane protein–associated protein B (VAPB), P56S, is genetically linked to familial ALS and related motor neuron disorders. VAPB is an endoplasmic reticulum (ER)–localized protein that regulates ER–organelle tethering, calcium homeostasis, and unfolded protein response. However, the molecular and cellular mechanisms by which the P56S mutation leads to selective CSMN degeneration remain poorly understood. We address this knowledge gap using a homozygous knock-in (KI) mouse model expressing mutant P56S VAPB. This model enables investigation of disease mechanisms in the context of intact mammalian brain architecture and corticospinal circuitry. Through integrated behavioral, histological, cellular, and molecular analyses, we link progressive CSMN degeneration to VAPB destabilization, inclusion formation, disruption of ER–mitochondria contacts, impaired VAPB–PTPIP51 and IP3R–VDAC interactions, dysregulated calcium signaling, and activation of pathological stress pathways. Specifically, we implicate the Ca²⁺–CaMKII–CRMP2 signaling cascade and the IRE1–p38 MAPK/JNK–tau/p53 pathway as key mediators of neuronal dysfunction and loss. By defining how the VAPB P56S mutation disrupts molecular networks and neural circuits to drive CSMN degeneration, this work provides a mechanistic framework for ALS pathogenesis. These insights may guide the development of targeted neuromodulatory or pharmacological strategies aimed at preserving CSMN function and slowing disease progression in ALS and related motor neuron diseases.