PI31 Is an Adaptor Protein for Proteasome Transport in Axons and Required for Synaptic Development

Liu, Kai; Jones, Sandra K.; Minis, Adi; Rodríguez, José Antonio; Molina, Henrik; Steller, Hermann

doi:10.1016/j.devcel.2019.06.009

Cited by 51 publications

(57 citation statements)

References 151 publications

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“…However, a role for PI31 in mediating the proteasome impairment and neuronal degeneration observed in Fbxo7/PARK15 mutants was dismissed based on results from cell culture experiments (33, 93). The current study, together with the work of Liu et al (2019), suggest that this topic deserves more careful examination (43). MEFs deficient for PI31 survived for extended periods of time, and we were unable to detect a major reduction of total proteasome activity in these cells.…”

Section: Discussionsupporting

confidence: 51%

“…Significantly, inactivation of PI31 in Drosophila blocks proteasome motility and disrupts synaptic protein homeostasis and structure. This function of PI31 is conserved from insects to mammals, since inactivation of PI31 in mouse hippocampal neurons impairs proteasome movement in axons as well (43). Although we have not yet been able to perform live cell imaging analyses to directly demonstrate a requirement of PI31 for proteasome movement in mouse motor neurons or Purkinje cells, impaired transport of proteasomes in axons and dendrites provides an attractive explanation for the observed defects in protein homeostasis at nerve endings.…”

Section: Discussionmentioning

confidence: 99%

“…According to our model, inactivation of PI31 leads to a shortage of proteasomes at synapses, which in turn causes the accumulation of poly-Ub proteins and p62-positive aggregates. It appears that backup clearance mechanisms, such as autophagy and possibly also shedding of microvesicles/exosomes, can partially compensate for the loss of PI31-mediated proteasome activity in PI31 mutants (6, 43, 86–90). The latter would also explain the gliosis that we observed already at P30 in PI31 fl/fl PCP2-Cre mice.…”

Section: Discussionmentioning

confidence: 99%

“…We also saw that PI31-Null MEFs had slight defects in proteasome assembly, as indicated by reduced numbers of single-capped 26S particles. Therefore, PI31 may regulate proteasomes by multiple mechanisms: through the assembly of functional 26S proteasomes from 19S and 20S particles, and via transport (29, 43). In any event, it appears that neurons are particularly sensitive to the loss of PI31 function, and a neuro-protective role of PI31 should not be ruled out based on results with non-neuronal immortalized cells.…”

Section: Discussionmentioning

confidence: 99%

“…We recently showed that in addition to its effect on proteasome assembly, PI31 is an adapter for neuronal proteasome transport, suggesting a key role in protein homeostasis and synaptic function (43). To examine the physiological function of PI31, we generated global and conditional knockout mouse strains and investigated how loss of PI31 affects two major types of neurons - spinal motor neurons (MNs) and cerebellar Purkinje cells (PCs).…”

Section: Introductionmentioning

confidence: 99%

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

Minis

Rodríguez

Levin

et al. 2019

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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. Statement 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. (26, 33, 34). Significantly, impaired UPS function and mutations in Fbxo7/PARK15 are associated with neurodegenerative diseases (33-42).We recently showed that in addition to its effect on proteasome assembly, PI31 is an adapter for neuronal proteasome transport, suggesting a key role in protein homeostasis and synaptic function (43). To examine the physiological function of PI31, we generated global and conditional knockout mouse strains and investigated how loss of PI31 affects two major types of neurons -spinal motor neurons (MNs) and cerebellar Purkinje cells (PCs). Spinal MNs reside in the ventral horn of the spinal cord, while their long axons, that can extend over one meter in humans, innervate effector muscles at a specialized synapse called the neuromuscular junction (NMJ) (44). PCs are the sole output neurons of the cerebellar cortex. Their dendrites receive inputs from cerebellar granule cell parallel fibers and inferior olivary nucleus climbing fibers, while their axons project through the inner granular layer (IGL) of the cerebellar cortex, where mature granule cells (GCs) and Golgi interneurons reside, to synapse onto deep cerebellar nuclei neurons (DCNn) in the deep cerebellar nuclei (DCN) (45, 46). Both of these neurons are also involved in a wide range of neurodegenerative diseases, including Amyotrophic Lateral Sclerosis (ALS) and Spinal Muscular Atrophy (SMA) in the c...

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Section: Discussionsupporting

confidence: 51%

Section: Discussionmentioning

confidence: 99%