Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 6 de 6
Filter
Add more filters










Database
Language
Publication year range
1.
Cell Rep ; 35(6): 109125, 2021 05 11.
Article in English | MEDLINE | ID: mdl-33979606

ABSTRACT

Spinal muscular atrophy (SMA) is a debilitating neurological disorder marked by degeneration of spinal motor neurons and muscle atrophy. SMA results from mutations in survival motor neuron 1 (SMN1), leading to deficiency of survival motor neuron (SMN) protein. Current therapies increase SMN protein and improve patient survival but have variable improvements in motor function, making it necessary to identify complementary strategies to further improve disease outcomes. Here, we perform a genome-wide RNAi screen using a luciferase-based activity reporter and identify genes involved in regulating SMN gene expression, RNA processing, and protein stability. We show that reduced expression of Transcription Export complex components increases SMN levels through the regulation of nuclear/cytoplasmic RNA transport. We also show that the E3 ligase, Neurl2, works cooperatively with Mib1 to ubiquitinate and promote SMN degradation. Together, our screen uncovers pathways through which SMN expression is regulated, potentially revealing additional strategies to treat SMA.


Subject(s)
Genetic Techniques/standards , Genomics/methods , High-Throughput Screening Assays/methods , Motor Neurons/metabolism , RNA Interference/physiology , Humans
2.
Cerebrum ; 20192019.
Article in English | MEDLINE | ID: mdl-32206168

ABSTRACT

Spinal muscular atrophy is the number one genetic cause of infant death. Until recently, half the babies born with it would die before their second birthdays, their hearts and lungs becoming too weak to continue. Medical care improved the odds somewhat, but new discoveries and therapeutic developments have improved survival rates significantly-and more good news may be on the horizon.

3.
Cell Stem Cell ; 23(1): 21-24, 2018 07 05.
Article in English | MEDLINE | ID: mdl-29887317

ABSTRACT

The genetic complexity, clinical variability, and inaccessibility of affected tissue in neurodegenerative and neuropsychiatric disorders have largely prevented the development of effective disease-modifying therapeutics. A precision medicine approach that integrates genomics, deep clinical phenotyping, and patient stem cell models may facilitate identification of underlying biological drivers and targeted drug development.


Subject(s)
Mental Disorders/therapy , Nervous System Diseases/therapy , Precision Medicine , Stem Cell Transplantation , Stem Cells/cytology , Humans , Mental Disorders/genetics , Mental Disorders/pathology , Nervous System Diseases/genetics , Nervous System Diseases/pathology
4.
J Clin Invest ; 128(7): 3008-3023, 2018 07 02.
Article in English | MEDLINE | ID: mdl-29672276

ABSTRACT

Spinal muscular atrophy (SMA), a degenerative motor neuron (MN) disease, caused by loss of functional survival of motor neuron (SMN) protein due to SMN1 gene mutations, is a leading cause of infant mortality. Increasing SMN levels ameliorates the disease phenotype and is unanimously accepted as a therapeutic approach for patients with SMA. The ubiquitin/proteasome system is known to regulate SMN protein levels; however, whether autophagy controls SMN levels remains poorly explored. Here, we show that SMN protein is degraded by autophagy. Pharmacological and genetic inhibition of autophagy increases SMN levels, while induction of autophagy decreases these levels. SMN degradation occurs via its interaction with the autophagy adapter p62 (also known as SQSTM1). We also show that SMA neurons display reduced autophagosome clearance, increased p62 and ubiquitinated proteins levels, and hyperactivated mTORC1 signaling. Importantly, reducing p62 levels markedly increases SMN and its binding partner gemin2, promotes MN survival, and extends lifespan in fly and mouse SMA models, revealing p62 as a potential new therapeutic target for the treatment of SMA.


Subject(s)
Muscular Atrophy, Spinal/drug therapy , Muscular Atrophy, Spinal/metabolism , SMN Complex Proteins/metabolism , Sequestosome-1 Protein/antagonists & inhibitors , Animals , Autophagy , Cells, Cultured , Disease Models, Animal , Gene Knockdown Techniques , HEK293 Cells , Humans , Mice , Mice, Inbred C57BL , Mice, Knockout , Motor Neurons/metabolism , Muscular Atrophy, Spinal/pathology , Mutation , Phenotype , Proteolysis , RNA, Small Interfering/genetics , SMN Complex Proteins/deficiency , SMN Complex Proteins/genetics , Sequestosome-1 Protein/genetics , Sequestosome-1 Protein/metabolism , Survival of Motor Neuron 1 Protein/antagonists & inhibitors , Survival of Motor Neuron 1 Protein/genetics , Survival of Motor Neuron 1 Protein/metabolism , TOR Serine-Threonine Kinases/metabolism
5.
Hum Mol Genet ; 22(20): 4074-83, 2013 Oct 15.
Article in English | MEDLINE | ID: mdl-23727836

ABSTRACT

Spinal muscular atrophy (SMA) is caused by mutations of the survival motor neuron 1 (SMN1) gene, retention of the survival motor neuron 2 (SMN2) gene and insufficient expression of full-length survival motor neuron (SMN) protein. Quinazolines increase SMN2 promoter activity and inhibit the ribonucleic acid scavenger enzyme DcpS. The quinazoline derivative RG3039 has advanced to early phase clinical trials. In preparation for efficacy studies in SMA patients, we investigated the effects of RG3039 in severe SMA mice. Here, we show that RG3039 distributed to central nervous system tissues where it robustly inhibited DcpS enzyme activity, but minimally activated SMN expression or the assembly of small nuclear ribonucleoproteins. Nonetheless, treated SMA mice showed a dose-dependent increase in survival, weight and motor function. This was associated with improved motor neuron somal and neuromuscular junction synaptic innervation and function and increased muscle size. RG3039 also enhanced survival of conditional SMA mice in which SMN had been genetically restored to motor neurons. As this systemically delivered drug may have therapeutic benefits that extend beyond motor neurons, it could act additively with SMN-restoring therapies delivered directly to the central nervous system such as antisense oligonucleotides or gene therapy.


Subject(s)
Endoribonucleases/antagonists & inhibitors , Motor Neurons/drug effects , Muscular Atrophy, Spinal/physiopathology , Quinazolines/pharmacology , Ribonucleoproteins, Small Nuclear/metabolism , Survival of Motor Neuron 1 Protein/metabolism , Animals , Central Nervous System/drug effects , Central Nervous System/metabolism , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Humans , Mice , Mice, Transgenic , Motor Neurons/physiology , Muscles/drug effects , Muscles/metabolism , Muscular Atrophy, Spinal/drug therapy , Muscular Atrophy, Spinal/genetics , Muscular Atrophy, Spinal/metabolism , Neuromuscular Junction/drug effects , Neuromuscular Junction/physiology , Quinazolines/administration & dosage , Quinazolines/pharmacokinetics , Survival of Motor Neuron 2 Protein/genetics , Survival of Motor Neuron 2 Protein/metabolism , Synaptic Transmission
6.
Hum Mol Genet ; 21(1): 185-95, 2012 Jan 01.
Article in English | MEDLINE | ID: mdl-21968514

ABSTRACT

Spinal muscular atrophy (SMA), a motoneuron disease caused by a deficiency of the survival of motor neuron (SMN) protein, is characterized by motoneuron loss and muscle weakness. It remains unclear whether widespread loss of neuromuscular junctions (NMJs) is involved in SMA pathogenesis. We undertook a systematic examination of NMJ innervation patterns in >20 muscles in the SMNΔ7 SMA mouse model. We found that severe denervation (<50% fully innervated endplates) occurs selectively in many vulnerable axial muscles and several appendicular muscles at the disease end stage. Since these vulnerable muscles were located throughout the body and were comprised of varying muscle fiber types, it is unlikely that muscle location or fiber type determines susceptibility to denervation. Furthermore, we found a similar extent of neurofilament accumulation at NMJs in both vulnerable and resistant muscles before the onset of denervation, suggesting that neurofilament accumulation does not predict subsequent NMJ denervation. Since vulnerable muscles were initially innervated, but later denervated, loss of innervation in SMA may be attributed to defects in synapse maintenance. Finally, we found that denervation was amendable by trichostatin A (TSA) treatment, which increased innervation in clinically relevant muscles in TSA-treated SMNΔ7 mice. Our findings suggest that neuromuscular denervation in vulnerable muscles is a widespread pathology in SMA, and can serve as a preparation for elucidating the biological basis of synapse loss, and for evaluating therapeutic efficacy.


Subject(s)
Disease Models, Animal , Mice , Muscle, Skeletal/innervation , Muscular Atrophy, Spinal/pathology , Neuromuscular Junction/surgery , Animals , Male , Mice, Knockout , Mice, Transgenic , Muscle Denervation , Muscle, Skeletal/pathology , Muscle, Skeletal/surgery , Muscular Atrophy, Spinal/metabolism , Muscular Atrophy, Spinal/surgery , Nerve Degeneration , Neuromuscular Junction/metabolism , Synapses/metabolism , Synapses/pathology
SELECTION OF CITATIONS
SEARCH DETAIL
...