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@ARTICLE{ScekicZahirovic:285456,
author = {Scekic-Zahirovic, Jelena and Antonucci, Stefano and
Wiesner, Diana and Ebner, Chiara and El Hajj, Hussein and
Aousji, Oumayma and Halablab, Kareen and Fan, Yiting and
Zelaya, Anneka and Yartas, Gizem and Baskar, Karthik and
Çakmak, E. Anastasia and Bayer, David and Sung, Hoon-Ki and
Dupuis, Luc and Park, Jeehye and Roselli, Francesco},
title = {{L}arge-scale mapping of the {MCH} network in {ALS} mice
reveals the vulnerability of dopaminergic and {GABA}ergic
neurons in zona incerta},
journal = {Acta Neuropathologica Communications},
volume = {14},
number = {1},
issn = {2051-5960},
address = {London},
publisher = {Biomed Central},
reportid = {DZNE-2026-00238},
pages = {46},
year = {2026},
abstract = {Weight loss and hypermetabolism are early and
prognostically significant features of amyotrophic lateral
sclerosis (ALS) and are associated with hypothalamic atrophy
and degeneration of melanin-concentrating hormone (MCH)
neurons that regulate energy balance. To investigate whether
MCH vulnerability arises from upstream network dysfunction,
we performed whole-brain retrograde rabies tracing in
SOD1G93A mice. We identified an early, selective loss of
monosynaptic inputs from the zona incerta (ZI), a
dopaminergic (DA)/gamma-aminobutyric acid (GABA)ergic
nucleus that preceded MCH neuron degeneration. Neurochemical
profiling confirmed the DA/GABAergic identity of these ZI
input neurons, and ZI/DAergic neurons later degenerated.
ALS-related pathology emerged early in the ZI, paralleling
pathology in the motor cortex, while anterograde mapping
revealed that motor cortical projections preferentially
targeted the ZI, linking vulnerable motor and metabolic
networks. Loss of ZI/DAergic neurons was observed in
conjunction with weight loss in non-SOD1 ALS models. These
findings identify the ZI as an early-affected node within
hypothalamic networks and suggest that disruption of
DA/GABAergic inputs to MCH neurons is associated with
subsequent MCH and DA neuronal vulnerability, degeneration
and metabolic imbalance in ALS.The online version contains
supplementary material available at
10.1186/s40478-026-02231-z.},
keywords = {Amyotrophic lateral sclerosis (Other) / Dopaminergic
neurons (Other) / Melanin-concentrating hormone neurons
(Other) / Monosynaptic rabies tracing (Other) / Weight loss
(Other) / Zona incerta (Other)},
cin = {AG Roselli},
ddc = {610},
cid = {I:(DE-2719)1910001},
pnm = {352 - Disease Mechanisms (POF4-352)},
pid = {G:(DE-HGF)POF4-352},
typ = {PUB:(DE-HGF)16},
doi = {10.1186/s40478-026-02231-z},
url = {https://pub.dzne.de/record/285456},
}