DOMINANT-NEGATIVE <EM>UBAP1</EM> MUTATIONS DRIVE SELECTIVE CORTICOSPINAL MOTOR NEURON DEGENERATION

Hereditary spastic paraplegias (HSPs) are a heterogeneous group of neurodegenerative disorders characterized by progressive lower limb spasticity and weakness, primarily due to axonal degeneration of corticospinal motor neurons (CSMNs) in the corticospinal tract (CST). Mutations in UBAP1 (ubiquitin-associated protein 1) cause autosomal-dominant SPG80, a pure form of HSP, but the underlying pathogenic mechanisms remain poorly understood. Here, we generated a transgenic SPG80 mouse model harboring patient-specific recurrent Ubap1 mutations, which faithfully recapitulate key clinical features, including progressive gait disturbances, hindlimb spasticity, and motor impairments as evaluated by behavioral testing. For comparison in behavioral tests, we also examined Ubap1 knockout mice, which model simple loss of function. Histological analyses revealed projection motor neuron degeneration in particular layer V of primary motor cortex (M1), while transmission electron microscopy (TEM) demonstrated axonal swelling and abnormal mitochondria, indicative of distal axonopathy. To confirm selective vulnerability of CSMNs, we employed tissue clearing combined with retrograde viral labeling, unambiguously showing progressive CST degeneration restricted to labeled corticospinal neurons. Our data reveals a dominant-negative effect of mutant UBAP1 rather than simple loss of function, disrupting CSMN and axonal integrity. These findings establish a robust preclinical platform for SPG80, provide direct evidence of selective CSMN pathology, and uncover novel insights into disease pathogenesis. This work highlights potential therapeutic avenues targeting selective neuronal vulnerability in HSP and other neurodegenerative diseases.