The effect of muscle-specific anchoring protein on the biology of the Neuromuscular system

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Principal Investigator: MOHAMMED  AKAABOUNE
Organization: UNIVERSITY OF MICHIGAN AT ANN ARBOR
Fiscal Year: 2024
Award: $426,301
Funding agency: National Institute of Neurological Disorders and Stroke

Stable and efficient synaptic transmission depends largely on the maintenance of a high
number/density of postsynaptic receptors at synaptic sites. At the neuromuscular junction
(NMJ), the synapse between spinal motor neurons and skeletal muscle cells, the mechanisms
that regulate the stability of postsynaptic nicotinic acetylcholine receptors (AChRs) over the
lifetime of animals remain largely unknown. Recent studies from our lab showed that αkap, a
non-kinase muscle anchoring protein encoded within the calcium/calmodulin kinase II α gene,
plays an important role in regulating the stability of nicotinic acetylcholine receptors (AChRs)
and the structural integrity of the NMJ. In view of these results, we propose in the first aim to
investigate the effect of αkap knockdown during the development of healthy neuromuscular
synapses. In the second aim we propose to investigate the effect of the gain of function of αkap
on the maturation and maintenance of compromised NMJs using mice deficient in the sub-
complex of the dystrophin glycoprotein complex (DGC) (α-syntrophin and α-dystrobrevin). In the
third aim we propose to investigate the molecular mechanistic link between the DGC sub-
complex/αkap/ the deubiquitinating protease USP9X and the stability of AChR stability in mice
deficient in α-syntrophin/α-dystrobrevin, and USP9X. The outcomes of these studies will be
relevant for many neuromuscular diseases where the number and density of AChRs are
compromised.

Terms: <20S Catalytic Proteasome><20S Core Proteasome><20S Proteasome><20S Proteosome><21+ years old><ACh Receptors><APF-1><ATP-Dependent Proteolysis Factor 1><Abscission><Acetylcholine Receptors><Adult><Adult Human><Affect><Animals><Biologic Models><Biological Models><Biology><Ca(2+)-Calmodulin Dependent Protein Kinase><CaMK><Calcium><Calcium/calmodulin-dependent protein kinase><Calmodulin-Dependent Protein Kinases><Calmodulin-Kinase><Cell Body><Cell surface><Cells><Cholinergic Receptors><Cholinoceptive Sites><Cholinoceptors><Complex><Data><Development><Dose><Dystrophin><Endocytosis><Esteroproteases><Excision><Exocytosis><Extirpation><Genes><Glycoproteins><Goals><HMG-20><High Mobility Protein 20><Impairment><In Vitro><Knock-out><Knockout><Life><Link><Macropain><Macroxyproteinase><Maintenance><Metabolic><Mice><Mice Mammals><Model System><Modeling><Molecular><Motor Cell><Motor Neurons><Multicatalytic Proteinase><Murine><Mus><Muscle><Muscle Cells><Muscle Fibers><Muscle Tissue><Mutant Strains Mice><Myocytes><Myoneural Junction><Myotubes><NAC precursor><Nervous System Diseases><Nervous System Disorder><Neural Transmission><Neurologic Disorders><Neurological Disorders><Neuromuscular Diseases><Neuromuscular Junction><Nicotinic Acetylcholine Receptors><Nicotinic Receptors><Outcome Study><PARK1 protein><PARK4 protein><Pathway interactions><Peptidases><Peptide Hydrolases><Phenotype><Play><Postsynaptic Membrane><Process><Prosome><Protease Gene><Proteases><Proteasome><Proteasome Endopeptidase Complex><Proteinases><Proteins><Proteolytic Enzymes><Proteosome><Receptor Protein><Removal><Rhabdomyocyte><Role><SNCA><SNCA protein><Scaffolding Protein><Shapes><Site><Skeletal Fiber><Skeletal Muscle><Skeletal Muscle Cell><Skeletal Muscle Fiber><Skeletal Myocytes><Spinal><Surgical Removal><Synapses><Synaptic><Synaptic Receptors><Synaptic Transmission><System><Testing><Time><Transcript><Transfection><Ubiquitin><Voluntary Muscle><Work><a-syn><a-synuclein><adult youth><adulthood><alpha synuclein><alpha synuclein gene><alpha-dystrobrevin><alpha-syntrophin><alphaSP22><asyn><calcium-calmodulin-dependent PK><calcium-calmodulin-dependent PK type II><calmodulin dependent protein kinase><de-ubiquitinase><de-ubiquitinating enzyme><density><developmental><gain of function><in vivo Model><knock-down><knockdown><loss of function><microtubule associated protein 2 kinase><motoneuron><mouse mutant><multicatalytic endopeptidase complex><muscular><myoneural disorder><neurological disease><neuromotor system><neuromuscular><neuromuscular degenerative disorder><neuromuscular disorder><neuromuscular system><new approaches><non A-beta component of AD amyloid><non A4 component of amyloid precursor><novel approaches><novel strategies><novel strategy><overexpress><overexpression><pathway><post-natal period><postnatal><postnatal period><postsynaptic><protein complex><protein kinase II><receptor><receptor density><receptor recycling><resection><shRNA><short hairpin RNA><small hairpin RNA><social role><synapse><synapse formation><synaptic pruning><synaptogenesis><syntrophin><syntrophin alpha1><syntrophin-1><trafficking><ubiquitin isopeptidase><ubiquitin-specific isopeptidase><young adult><young adulthood><α synuclein gene><α-dystrobrevin><α-syn><α-syntrophin><α-synuclein>