TY  - JOUR
A1  - Andreska, Thomas
A1  - Lüningschrör, Patrick
A1  - Wolf, Daniel
A1  - McFleder, Rhonda L.
A1  - Ayon-Olivas, Maurilyn
A1  - Rattka, Marta
A1  - Drechsler, Christine
A1  - Perschin, Veronika
A1  - Blum, Robert
A1  - Aufmkolk, Sarah
A1  - Granado, Noelia
A1  - Moratalla, Rosario
A1  - Sauer, Markus
A1  - Monoranu, Camelia
A1  - Volkmann, Jens
A1  - Ip, Chi Wang
A1  - Stigloher, Christian
A1  - Sendtner, Michael
T1  - DRD1 signaling modulates TrkB turnover and BDNF sensitivity in direct pathway striatal medium spiny neurons
JF  - Cell Reports
N2  - Highlights
• Dopamine receptor-1 activation induces TrkB cell-surface expression in striatal neurons
• Dopaminergic deficits cause TrkB accumulation and clustering in the ER
• TrkB clusters colocalize with cargo receptor SORCS-2 in direct pathway striatal neurons
• Intracellular TrkB clusters fail to fuse with lysosomes after dopamine depletion

Summary
Disturbed motor control is a hallmark of Parkinson’s disease (PD). Cortico-striatal synapses play a central role in motor learning and adaption, and brain-derived neurotrophic factor (BDNF) from cortico-striatal afferents modulates their plasticity via TrkB in striatal medium spiny projection neurons (SPNs). We studied the role of dopamine in modulating the sensitivity of direct pathway SPNs (dSPNs) to BDNF in cultures of fluorescence-activated cell sorting (FACS)-enriched D1-expressing SPNs and 6-hydroxydopamine (6-OHDA)-treated rats. DRD1 activation causes enhanced TrkB translocation to the cell surface and increased sensitivity for BDNF. In contrast, dopamine depletion in cultured dSPN neurons, 6-OHDA-treated rats, and postmortem brain of patients with PD reduces BDNF responsiveness and causes formation of intracellular TrkB clusters. These clusters associate with sortilin related VPS10 domain containing receptor 2 (SORCS-2) in multivesicular-like structures, which apparently protects them from lysosomal degradation. Thus, impaired TrkB processing might contribute to disturbed motor function in PD.
KW  - motor learning
KW  - cortico-striatal synapse
KW  - basal ganglia
KW  - direct pathway
KW  - DRD1
KW  - dSPN
KW  - BDNF
KW  - TrkB
KW  - synaptic plasticity
KW  - GPCR
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-349932
VL  - 42
IS  - 6
ER  - 
TY  - JOUR
A1  - Dekker, Annelot M.
A1  - Diekstra, Frank P.
A1  - Pulit, Sara L.
A1  - Tazelaar, Gijs H. P.
A1  - van der Spek, Rick A.
A1  - van Rheenen, Wouter
A1  - van Eijk, Kristel R.
A1  - Calvo, Andrea
A1  - Brunetti, Maura
A1  - Van Damme, Philip
A1  - Robberecht, Wim
A1  - Hardiman, Orla
A1  - McLaughlin, Russell
A1  - Chiò, Adriano
A1  - Sendtner, Michael
A1  - Ludolph, Albert C.
A1  - Weishaupt, Jochen H.
A1  - Pardina, Jesus S. Mora
A1  - van den Berg, Leonard H.
A1  - Veldink, Jan H.
T1  - Exome array analysis of rare and low frequency variants in amyotrophic lateral sclerosis
JF  - Scientific Reports
N2  - Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects 1 in ~350 individuals. Genetic association studies have established ALS as a multifactorial disease with heritability estimated at ~61%, and recent studies show a prominent role for rare variation in its genetic architecture. To identify rare variants associated with disease onset we performed exome array genotyping in 4,244 cases and 3,106 controls from European cohorts. In this largest exome-wide study of rare variants in ALS to date, we performed single-variant association testing, gene-based burden, and exome-wide individual set-unique burden (ISUB) testing to identify single or aggregated rare variation that modifies disease risk. In single-variant testing no variants reached exome-wide significance, likely due to limited statistical power. Gene-based burden testing of rare non-synonymous and loss-of-function variants showed NEK1 as the top associated gene. ISUB analysis did not show an increased exome-wide burden of deleterious variants in patients, possibly suggesting a more region-specific role for rare variation. Complete summary statistics are released publicly. This study did not implicate new risk loci, emphasizing the immediate need for future large-scale collaborations in ALS that will expand available sample sizes, increase genome coverage, and improve our ability to detect rare variants associated to ALS.
KW  - amyotrophic lateral sclerosis
KW  - genome-wide association studies
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-223686
VL  - 9
ER  -