Spastin depletion increases tubulin polyglutamylation and impairs kinesin-mediated neuronal transport, leading to working and associative memory deficits
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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.
In: PLOS BIOL, Vol. 18, No. 8, 31.08.2020, p. e3000820.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Spastin depletion increases tubulin polyglutamylation and impairs kinesin-mediated neuronal transport, leading to working and associative memory deficits
AU - Lopes, André T
AU - Hausrat, Torben J
AU - Heisler, Frank F
AU - Gromova, Kira V
AU - Lombino, Franco L
AU - Fischer, Timo
AU - Ruschkies, Laura
AU - Breiden, Petra
AU - Thies, Edda
AU - Hermans-Borgmeyer, Irm
AU - Schweizer, Michaela
AU - Schwarz, Jürgen R
AU - Lohr, Christian
AU - Kneussel, Matthias
PY - 2020/8/31
Y1 - 2020/8/31
N2 - 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 α-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.
AB - 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 α-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.
KW - Action Potentials
KW - Animals
KW - Cell Membrane/metabolism
KW - Dendritic Spines/metabolism
KW - Excitatory Postsynaptic Potentials
KW - Glutamic Acid/metabolism
KW - Hippocampus/pathology
KW - Kinesin/metabolism
KW - Memory Disorders/metabolism
KW - Memory, Short-Term
KW - Mice, Knockout
KW - Microtubules/metabolism
KW - Motor Activity
KW - Neurons/metabolism
KW - Protein Transport
KW - Spastin/deficiency
KW - Synapses/metabolism
KW - Synaptic Vesicles/metabolism
KW - Tubulin/metabolism
U2 - 10.1371/journal.pbio.3000820
DO - 10.1371/journal.pbio.3000820
M3 - SCORING: Journal article
C2 - 32866173
VL - 18
SP - e3000820
JO - PLOS BIOL
JF - PLOS BIOL
SN - 1544-9173
IS - 8
ER -