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Spastin depletion increases tubulin polyglutamylation and impairs kinesin-mediated neuronal transport, leading to working and associative memory deficits

Lopes, André T. ; Hausrat, Torben J. ; Heisler, Frank F. ; Gromova, Kira V. ; Lombino, Franco L. ; Fischer, Timo ; Ruschkies, Laura ; Breiden, Petra ; Thies, Edda ; Hermans-Borgmeyer, Irm ; Schweizer, Michaela ; Schwarz, Jürgen R. ; Lohr, Christian ; Kneussel, Matthias Scheiffele, Peter

PLoS Biology, 2020-08, Vol.18 (8), p.e3000820-e3000820 [Periódico revisado por pares]

San Francisco: Public Library of Science

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Título:
Spastin depletion increases tubulin polyglutamylation and impairs kinesin-mediated neuronal transport, leading to working and associative memory deficits
Autor: Lopes, André T. ; Hausrat, Torben J. ; Heisler, Frank F. ; Gromova, Kira V. ; Lombino, Franco L. ; Fischer, Timo ; Ruschkies, Laura ; Breiden, Petra ; Thies, Edda ; Hermans-Borgmeyer, Irm ; Schweizer, Michaela ; Schwarz, Jürgen R. ; Lohr, Christian ; Kneussel, Matthias
Scheiffele, Peter
Assuntos: Animal cognition ; Associative memory ; Axonal transport ; Biology and Life Sciences ; Cargo transportation ; Cognition ; Cognitive ability ; Dementia disorders ; Depletion ; Etiology ; Gene expression ; Genetic aspects ; Health aspects ; Hereditary spastic paraplegia ; Investigations ; Kinesin ; Medicine and Health Sciences ; Memory ; Memory disorders ; Microtubules ; Mutants ; Mutation ; Nervous system ; Neurobiology ; Neurodegeneration ; Neurons ; Neurophysiology ; Neurosciences ; Paralysis ; Paraplegia ; Paraplegics ; Physiological aspects ; Post-translational modifications ; Proteins ; Ribonucleic acid ; Risk factors ; RNA ; Software ; Spastic paraplegia ; Spasticity ; Supervision ; Synapses ; Tubulin ; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid
É parte de: PLoS Biology, 2020-08, Vol.18 (8), p.e3000820-e3000820
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The authors have declared that no competing interests exist.
Descrição: Mutations in the gene encoding the microtubule-severing protein spastin (spastic paraplegia 4 [SPG4]) cause hereditary spastic paraplegia (HSP), associated with neurodegeneration, spasticity, and motor impairment. Complicated forms (complicated HSP [cHSP]) further include cognitive deficits and dementia; however, the etiology and dysfunctional mechanisms of cHSP have remained unknown. Here, we report specific working and associative memory deficits upon spastin depletion in mice. Loss of spastin-mediated severing leads to reduced synapse numbers, accompanied by lower miniature excitatory postsynaptic current (mEPSC) frequencies. At the subcellular level, mutant neurons are characterized by longer microtubules with increased tubulin polyglutamylation levels. Notably, these conditions reduce kinesin-microtubule binding, impair the processivity of kinesin family protein (KIF) 5, and reduce the delivery of presynaptic vesicles and postsynaptic [alpha]-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. Rescue experiments confirm the specificity of these results by showing that wild-type spastin, but not the severing-deficient and disease-associated K388R mutant, normalizes the effects at the synaptic, microtubule, and transport levels. In addition, short hairpin RNA (shRNA)-mediated reduction of tubulin polyglutamylation on spastin knockout background normalizes KIF5 transport deficits and attenuates the loss of excitatory synapses. Our data provide a mechanism that connects spastin dysfunction with the regulation of kinesin-mediated cargo transport, synapse integrity, and cognition.
Editor: San Francisco: Public Library of Science
Idioma: Inglês

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Spastin depletion increases tubulin polyglutamylation and impairs kinesin-mediated neuronal transport, leading to working and associative memory deficits

Lopes, André T. ; Hausrat, Torben J. ; Heisler, Frank F. ; Gromova, Kira V. ; Lombino, Franco L. ; Fischer, Timo ; Ruschkies, Laura ; Breiden, Petra ; Thies, Edda ; Hermans-Borgmeyer, Irm ; Schweizer, Michaela ; Schwarz, Jürgen R. ; Lohr, Christian ; Kneussel, Matthias Scheiffele, Peter

San Francisco: Public Library of Science

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