Biology subjects

Minis, A.

Publications and source records attributed to Minis, A..

3 recordsLinked to original sources

bioRxiv2020

PI31 expression prevents neuronal degeneration in a mouse Parkinson Disease model

Age-related neurodegenerative diseases pose a major unmet health need since no effective treatment strategies are currently available. These disorders are defined by the accumulation of abnormal protein aggregates that impair synaptic function and cause progressive neuronal degeneration. Therefore, stimulating protein clearance mechanisms may be neuro-protective. The proteasome regulator PI31 promotes local protein degradation at synapses by mediating fast proteasome transport in neurites, and loss of PI31 function causes neuronal degeneration. Here we show that transgenic expression of PI31 in a mouse Parkinsons Disease model preserves neuronal function and greatly extends animal health and lifespan. These results indicate that targeting the PI31-pathway may have therapeutic value for treating neurodegenerative disorders.

neuroscience↗

bioRxiv2019

The proteasome regulator PI31 is required for protein homeostasis, synapse maintenance and neuronal survival in mice

Proteasome-mediated degradation of intracellular proteins is essential for cell function and survival. The proteasome-binding protein PI31 (Proteasomal Inhibitor of 31kD) promotes 26S assembly and functions as an adapter for proteasome transport in axons. As localized protein synthesis and degradation is especially critical in neurons, we generated a conditional loss of PI31 in spinal motor neurons (MNs) and cerebellar Purkinje cells (PCs). A cKO of PI31 in these neurons caused axon degeneration, neuronal loss and progressive spinal and cerebellar neurological dysfunction. For both MNs and PCs, markers of proteotoxic stress preceded axonal degeneration and motor dysfunction, indicating a critical role for PI31 in neuronal homeostasis. The time course of the loss of MN and PC function in developing mouse CNS suggests a key role for PI31 in human developmental neurological disorders.\n\nStatement of SignificanceThe conserved proteasome-binding protein PI31 serves as an adapter to couple proteasomes with cellular motors to mediate their transport to distal tips of neurons where protein breakdown occurs. We generated global and conditional PI31 knockout mouse strains and show that this protein is required for protein homeostasis, and that its conditional inactivation in neurons disrupts synaptic structures and long-term survival. This work establishes a critical role for PI31 and local protein degradation in the maintenance of neuronal architecture, circuitry and function. Because mutations that impair PI31 function cause neurodegenerative diseases in humans, reduced PI31 activity may contribute to age-related neurodegenerative diseases.

neuroscience↗

bioRxiv2018

PI31 is an adaptor protein for proteasome transport in axons

Protein degradation by the ubiquitin-proteasome system (UPS) is critical for neuronal development, plasticity and function. Neurons utilize microtubule-dependent molecular motors to allocate proteasomes to synapses, but how proteasomes are coupled to motor proteins and how this transport is regulated to meet changing demand for protein breakdown remains largely unknown. We show that the conserved proteasome-binding protein PI31 serves as an adaptor to directly couple proteasomes with dynein light chain proteins (DYNLL1/2). Inactivation of PI31 inhibits proteasome motility in axons and disrupts synaptic protein homeostasis, structure and function. Moreover, phosphorylation of PI31 at a conserved site by p38 MAP kinase promotes binding to DYNLL1/2, and a non-phosphorable PI31 mutant impairs proteasome movement in axons, suggesting a mechanism to regulate loading of proteasomes onto motor proteins. Because mutations affecting PI31 activity are associated with human neurodegenerative diseases, impairment of PI31-mediated axonal transport of proteasomes may be the root cause of these disorders.

cell biology↗