Reply to “Concerns regarding the interpretation of Shank3 protein isoforms expressed in Shank3B−/− mice: potential off-target effects by a neomycin resistance cassette”

Molecular Psychiatry, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 22, 2025

Language: Английский

---

N-acetyl-l-leucine lowers pS129-synuclein and improves synaptic function in models of Parkinson’s disease

Published: April 9, 2025

N-acetyl-L-leucine (NALL), a derivative of the branched-chain amino acid leucine, has shown therapeutic potential in neurodegenerative diseases, including prodromal stages Parkinson’s disease (PD). However, mechanism its protective effects been largely unknown. Using discovery-based proteomics, we found that treatment with NALL led to upregulation lysosomal, mitochondrial, and synaptic proteins PD patient-derived dopaminergic neurons. reduced levels pathological pS129-alpha-synuclein neurons from patients harboring GBA1 or LRRK2 mutations. This decrease pS129-syn was dependent on serine protease HTRA1 induced by also upregulated expression wild-type parkin both mutant neurons, leading an increase functional dopamine transporter membrane-associated synaptojanin-1, suggesting improved function. Furthermore, LRRK2^R1441C knock-in mice decreased pS129-alpha-synuclein, increased dopamine-dependent motor learning deficits. These findings highlight α-synuclein pathology function vulnerable

Language: Английский

---

Concerns regarding the interpretation of Shank3 protein isoforms expressed in Shank3B-/- mice: potential off-target effects by a neomycin resistance cassette

Molecular Psychiatry, Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 27, 2024

Language: Английский

---

Shank3 deficiency alters midbrain GABAergic neuron morphology, GABAergic markers and synaptic activity in primary striatal neurons

Molecular Brain, Journal Year: 2024, Volume and Issue: 17(1)

Published: Sept. 27, 2024

Abstract Abnormalities in gamma-aminobutyric acid (GABA)ergic neurotransmission play a role the pathogenesis of autism, although mechanisms responsible for alterations specific brain regions remain unclear. Deficits social motivation and interactions are core symptoms likely due to defects dopaminergic neural pathways. Therefore, investigating morphology functional roles GABAergic neurons within projection areas could elucidate underlying etiology autism. The aim this study was (1) compare arborization glutamate decarboxylase (GAD)-positive from midbrain tegmentum; (2) evaluate synaptic activity primary striatum; (3) assess postsynaptic puncta ventral striatum wild-type (WT) Shank3 -deficient mice. We found significant decrease number short neurites GAD positive tegmentum application blocker GABA A receptors (GABA R) revealed significantly increased frequency spontaneous currents (sPSCs) striatal compared their WT counterparts. mean absolute amplitude events higher also observed reduction gephyrin/GABA R γ2 colocalization adult male gene expression collybistin lower nucleus accumbens while gephyrin were tegmental area (VTA) Shank3- deficient In conclusion, deficiency leads impaired function areas. These changes may underlie autistic symptoms, potential interventions modulating pathways represent new treatment modality.

Language: Английский

---

Reduced Neurite Arborization in Primary Dopaminergic Neurons in Autism-Like Shank3B-Deficient Mice

Molecular Neurobiology, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 9, 2024

Language: Английский

---