The Contribution of Neurogenetics in Disentangling the Pathophysiology of Neurodegenerative Diseases

A special issue of Life (ISSN 2075-1729). This special issue belongs to the section "Physiology and Pathology".

Deadline for manuscript submissions: 31 March 2026 | Viewed by 1200

Special Issue Editors


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Guest Editor
1. Clinical Neurophysiology Research Unit, Oasi Research Institute-IRCCS, Troina, Italy
2. Department of Surgery and Medical-Surgical Specialties, University of Catania, Catania, Italy
Interests: translational neurophysiology; neuroimaging; neurodegenerative diseases; cognitive neuroscience; neuroplasticity; neuromodulation; sleep disorders
Special Issues, Collections and Topics in MDPI journals

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Guest Editor
Oasi Research Institute-IRCCS, Via Conte Ruggero 73, 94018 Troina, Italy
Interests: neurogenetics; neurodegenerative diseases; neurodevelopmental disorders; rare diseases; genomics; transcriptomics; proteomics; methylomics

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Guest Editor
Oasi Research Institute-IRCCS, Via Conte Ruggero 73, 94018 Troina, Italy
Interests: neurodegenerative diseases; genetics; innovation in neurodegeneration research; transcriptomics; Parkinson’s disease; Huntington’ disease; autism

Special Issue Information

Dear Colleagues,

Neurodegenerative diseases represent an increasingly pressing global health challenge, especially in middle- and high-income countries, significantly contributing to the increase in mortality rates and the burden of Disability-Adjusted Life Years (DALYs). The ‘undoing’ present at the level of neuronal networks and on neurons, as well as the accumulation of protein aggregates, are crucial factors that have been recognized, to date, as the primary causes of cognitive, sensory, and motor dysfunction. Therefore, while waiting for disease-modifying drugs to be available, the possibility to quickly detect, promptly manage, and reliably monitor neurodegenerative diseases is of pivotal importance to prevent complication, maintain functional independence, and ensure an adequate quality of life. The identification of a prodromal phase in some of these disorders offers a valuable “window of opportunity” for making a powerful impact on disease onset and progression. To effectively address this challenge, an approach that recognizes neurodegeneration as an inherently cellular and molecular process is essential. In this complex scenario, translational neurogenetics emerges as the key discipline to achieve our goals by integrating genetic discoveries with clinical practice. For these reasons, we propose this Special Issue with the aim to compile high-quality original papers and comprehensive reviews of the literature that will make a significant and innovative contribution to the understanding and treatment of neurodegenerative diseases through the “looking glass” of neurogenetics. Translationally, this will positively transform the landscape of these diseases, which negatively affect the lives of millions of people, through a better understanding of their pathogenic bases and pathophysiological mechanisms.

Prof. Dr. Giuseppe Lanza
Dr. Michele Salemi
Dr. Francesca Schillaci
Guest Editors

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Keywords

  • neurodegenerative diseases
  • translational neurogenetics
  • early diagnosis
  • prevention
  • therapies
  • clinical practice
  • advanced genetic techniques
  • outcome measures

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Published Papers (1 paper)

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Review

22 pages, 588 KB  
Review
Chloride Homeostasis in Neuronal Disorders: Bridging Measurement to Therapy
by Daniele Arosio and Carlo Musio
Life 2025, 15(9), 1461; https://doi.org/10.3390/life15091461 - 17 Sep 2025
Viewed by 991
Abstract
Neuronal chloride (Cl) homeostasis is fundamental for brain function, with disruptions increasingly recognized as pathogenic across neurological disorders. This review synthesizes evidence from preclinical models and clinical studies, integrating electrophysiological measurements, molecular analyses, imaging with genetically encoded sensors like ClopHensor, and [...] Read more.
Neuronal chloride (Cl) homeostasis is fundamental for brain function, with disruptions increasingly recognized as pathogenic across neurological disorders. This review synthesizes evidence from preclinical models and clinical studies, integrating electrophysiological measurements, molecular analyses, imaging with genetically encoded sensors like ClopHensor, and behavioral assays. Key findings demonstrate that Cl dysregulation follows distinct patterns: (1) in epilepsy, KCC2 downregulation converts GABAergic inhibition to excitation, promoting seizures; (2) in Alzheimer’s disease (AD) models, pre-symptomatic KCC2 loss in hippocampus is observed, with KCC2 restoration reversing aspects of cognitive decline; (3) in autism spectrum disorders (ASD), developmental delays in GABA polarity shifts feature due to altered NKCC1/KCC2 ratios; and (4) in Huntington’s disease (HD), striatal neuron-specific Cl imbalances are linked to motor dysfunction. Methodologically, advanced tools—including subcellular Cl imaging and high-throughput drug screening—have enabled precise dissection of these mechanisms. Therapeutic strategies targeting Cl transporters (NKCC1 inhibitors like bumetanide, KCC2 enhancers like CLP290) show preclinical promise but require improved central nervous system (CNS) delivery and selectivity. These findings establish Cl homeostasis as both a biomarker and therapeutic target, necessitating precision medicine approaches to address heterogeneity in neurological disorders. Full article
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