Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UMLS:C0085584 (
encephalopathy
)
18,178
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Deletion of
Mapt
, encoding the
microtubule-binding protein
Tau, prevents disease in multiple genetic models of hyperexcitability. To investigate whether the effect of Tau depletion is generalizable across multiple sodium channel gene-linked models of epilepsy, we examined the
Scn1b
-/-
mouse model of Dravet syndrome, and the
Scn8a
N1768D/+
model of Early Infantile Epileptic
Encephalopathy
. Both models display severe seizures and early mortality. We found no prolongation of survival between
Scn1b
-/-
,Mapt
+/+
,
Scn1b
-/-
,Mapt
+/-,
or
Scn1b
-/-
,Mapt
-/-
mice or between
Scn8a
N1768D/+
,Mapt
+/+
,
Scn8a
N1768D/+
,Mapt
+/-
, or
Scn8a
N1768D/+
,Mapt
-/-
mice. Thus, the effect of
Mapt
deletion on mortality in epileptic
encephalopathy
models is gene specific and provides further mechanistic insight.
...
PMID:
Mapt
deletion fails to rescue premature lethality in two models of sodium channel epilepsy. 3012 23
Chronic traumatic
encephalopathy
(CTE) is a progressive neurodegenerative disorder caused by repetitive trauma to the central nervous system (CNS) suffered by soldiers, contact sport athletes, and civilians following accident-related trauma. CTE is a CNS tauopathy, with trauma-induced inflammation leading to accumulation of hyperphosphorylated forms of the
microtubule-binding protein
Tau (pTau), resulting in neurofibrillary tangles and progressive loss of neurons. At present, there are no therapies to treat CTE. We hypothesized that direct CNS administration of an adeno-associated virus (AAV) vector coding for an anti-pTau antibody would generate sufficient levels of anti-pTau in the CNS to suppress pTau accumulation thus interrupting the pathogenic process. Using a serotype AAVrh.10 gene transfer vector coding for a monoclonal antibody directed against pTau, we demonstrate the feasibility of this strategy in a murine CTE model in which pTau accumulation was elicited by repeated traumatic brain injury (TBI) using a closed cortical impact procedure over 5 days. Direct delivery of AAVrh.10 expression vectors coding for either of the two different anti-pTau antibodies to the hippocampus of these TBI mice significantly reduced pTau levels across the CNS. Using doses that can be safely scaled to humans, the data demonstrate that CNS administration of AAVrh.10anti-pTau is effective, providing a new strategy to interrupt the CTE consequences of TBI.
...
PMID:Anti-Phospho-Tau Gene Therapy for Chronic Traumatic Encephalopathy. 3160 4
Classical dynamins are large GTPases regulating membrane and cytoskeleton dynamics, and they are linked to different pathological conditions ranging from neuromuscular diseases to
encephalopathy
and cancer. Dominant
dynamin 2
(
DNM2
) mutations lead to either mild adult onset or severe autosomal dominant centronuclear myopathy (ADCNM). Our objectives were to better understand the pathomechanism of severe ADCNM and test a potential therapy. Here, we created the Dnm2SL/+ mouse line harboring the common S619L mutation found in patients with severe ADCNM and impairing the conformational switch regulating dynamin self-assembly and membrane remodeling. The Dnm2SL/+ mouse faithfully reproduces severe ADCNM hallmarks with early impaired muscle function and force, together with myofiber hypotrophy. It revealed swollen mitochondria lacking cristae as the main ultrastructural defect and potential cause of the disease. Patient analysis confirmed this structural hallmark. In addition,
DNM2
reduction with antisense oligonucleotides after disease onset efficiently reverted locomotor and force defects after only 3 weeks of treatment. Most histological defects including mitochondria alteration were partially or fully rescued. Overall, this study highlights an efficient approach to revert the severe form of dynamin-related centronuclear myopathy. These data also reveal that the dynamin conformational switch is key for muscle function and should be targeted for future therapeutic developments.
...
PMID:Physiological impact and disease reversion for the severe form of centronuclear myopathy linked to dynamin. 3280 72
