It is shown that microglia generated from FRDA patient-derived iPSCs exhibit a cell-autonomous pro-inflammatory phenotype in the absence of exogenous inflammatory stimuli.
Abstract
Friedreich Ataxia (FRDA) is an autosomal recessive neurodegenerative disorder characterized by progressive loss of cerebellar and proprioceptive neurons that control movement and coordination. In most patients, FRDA is caused by homozygous GAA trinucleotide repeat expansions in the first intron of the frataxin (FXN) gene, resulting in reduced expression of frataxin, a mitochondrial protein essential for biogenesis of iron-sulfur clusters and mitochondrial function. Although recent therapeutic advances have provided modest clinical benefit, effective disease-modifying treatments remain lacking. Increasing evidence indicates that microglial cell dysfunction contributes to FRDA pathogenesis, highlighting these cells as potential therapeutic targets. However, the molecular mechanisms underlying FXN-deficient microglial dysfunction remain poorly understood. Here, we show that microglia generated from FRDA patient-derived iPSCs exhibit a cell-autonomous pro-inflammatory phenotype in the absence of exogenous inflammatory stimuli. This phenotype is characterized by coordinated activation of immune transcriptional programs, dysregulated secretion of neuroinflammatory proteins, impaired autophagy-lysosomal function, and activation of inflammasomes pathways involving NLRP2 and NLRP3. These findings demonstrate that FXN deficiency is sufficient to induce intrinsic microglial activation and identify molecular pathways that may represent attractive targets for future FRDA therapies.
Neuroinflammation strongly contributes to the pathogenesis of neurological and neurodegenerative diseases, including Parkinson’s disease (PD). We show that ablation of Usp15 in astrocytes and in microglia protects against lethal neuroinflammation in vivo. In a mouse model of synucleinopathy, Usp15 deletion diminishes α-syn deposits in the brain, slows disease progression, and increases survival time. The neuroprotective effect of Usp15 is associated with differential expression of inflammatory pathways in situ including interferon stimulated genes. These USP15-dependent effects in vivo are recapitulated in vitro in primary human microglia and astrocytes. We detect high USP15 expression in microglia from Parkinson’s patients with strong co-expression with LRRK2 and SNCA. In humans, we detect a strong cis-acting eQTL directing high USP15 expression in CD14+ myeloid cells. The allele driving this eQTL is itself associated with increased disease risk, linking myeloid USP15 expression, elevated USP15 plasma levels in Parkinson’s patients, to genetic susceptibility.
Nassima Fodil, E. del Cid-Pellitero, V. Piscopo et al.· bioRxiv· 0 citations
INTRODUCTION
HD is a hereditary neurodegenerative disease caused by the amplification of the CAG trinucleotide repeat in the HTT gene, leading to a Mutant Huntingtin (mHTT) protein that dysregulates transcription, promotes protein aggregation, induces neuroinflammation, and impairs mitochondrial function. Motor dysfunction, cognitive decline, and mental disorders are manifestations of these biochemical abnormalities. Effective disease-modifying treatments are still limited, even with recent improvements. This review investigates the increasing relevance of Klotho, an anti-aging protein with neuroprotective, antioxidant, and anti-inflammatory characteristics, as a possible therapeutic target in Huntington disease.
METHODS
We did a comprehensive literature search across PubMed, Scopus, and Web of Science databases. Klotho's molecular functions in neural protection, energy metabolism, oxidative stress reduction, and anti-inflammatory signalling were investigated in the context of HD pathogenesis.
RESULTS
Klotho appears to influence critical neurodegenerative processes involved in HD. It inhibits NF-κB and NLRP3 inflammasome activity, stimulates antioxidant enzyme expression (SOD, catalase), promotes GluN2B-NMDA receptor-mediated synaptic plasticity, and increases astrocytic aerobic glycolysis via FGFR1-ERK signaling. These functions may mitigate mHTT- induced neuronal damage. Pharmacologic treatments (e.g., PPAR-γ agonists), vitamin D, and lifestyle interventions can all modulate klotho expression.
DISCUSSION
Klotho exhibits neuroprotective effects in Huntington's disease by reducing NF-κB/NLRP3- mediated inflammation, strengthening antioxidant defenses, promoting GluN2B-NMDA- dependent synaptic plasticity, and improving astrocytic metabolic support via FGFR1-ERK signaling. One intriguing treatment approach for mutant huntingtin-induced neurotoxicity is the modification of klotho expression.
CONCLUSION
Klotho is a promising neurochemical modulator with disease-modifying properties in HD. Its multifunctional protective activities are consistent with important pathological markers of HD, necessitating more preclinical and clinical studies to confirm its translational value.
Shikha Singh, Avnesh Kumar, Falguni Goel et al.· Current molecular medicine· 0 citations
Repeat expansion cerebellar ataxias comprise a genetically and mechanistically heterogeneous group of neurodegenerative disorders unified by the pathological expansion of short tandem repeats (STRs) beyond a disease-causing threshold. Depending on their genomic localization, these expansions can lead to toxic protein gain-of-function, as in polyglutamine (polyQ) cerebellar ataxias, or to RNA-mediated toxicity and repeat-associated non-AUG (RAN) translation, for which recent evidence supports a major pathogenic role in non-coding spinocerebellar ataxias (SCAs). Despite these distinct upstream mechanisms, disruption of neuronal homeostasis occurs through converging pathogenic processes, including proteostasis impairment, transcriptional dysregulation, and mitochondrial dysfunction, leading to progressive neuronal loss. Importantly, impaired autophagy has been consistently reported across multiple repeat expansion ataxias, including both dominant SCAs and recessive conditions, such as Friedreich’s ataxia, suggesting that impairment of this pathway may represent a shared downstream event in disease progression. Indeed, in polyQ cerebella ataxias, the accumulation of misfolded and aggregation-prone proteins places a substantial burden on cellular quality control systems, particularly the ubiquitin-proteasome system and autophagy. Similarly, in non-coding SCAs, toxic RNA species and RAN-derived peptides might interfere with protein clearance mechanisms and contribute to cellular stress. In this review, we will discuss the evidence supporting autophagy impairment as a convergent pathogenic pathway in repeat expansion cerebellar ataxias.
Silvia Tortoriello, Simona Rossi, I. Della Valle et al.· Cells· 0 citations
Friedreich ataxia (FA) is a progressive neurodegenerative disorder caused by reduced expression of frataxin (FXN), a mitochondrial protein essential for iron-sulfur (Fe-S) cluster biogenesis. Although gene therapy strategies aimed at restoring FXN have shown promise, excessive expression can lead to mitochondrial dysfunction, emphasizing the importance of maintaining FXN within a physiological range. Here, we evaluated a gene therapy approach based on a human mini-frataxin construct (miniFXN7) incorporating an endogenous regulatory element to enable controlled FXN expression. The construct was delivered systemically using an AAV-PHP.eB vector in the Pvalb-cKO mouse model of FA. MiniFXN7 treatment resulted in widespread neuronal transduction and restoration of FXN expression toward a near-physiological range in the neuronal populations examined. Treated mice exhibited sustained improvements in motor coordination and proprioceptive function, including normalization of H-reflex responses. At the cellular level, miniFXN7 restored succinate dehydrogenase activity, a mitochondrial Fe-S enzyme, and was associated with partial normalization of mitochondrial morphology. In parallel, neuronal integrity was preserved and astrogliosis reduced across the cerebellum. These findings demonstrate that physiologically regulated FXN replacement is sufficient to achieve substantial functional rescue in FA, supporting a gene therapy strategy based on a transgene expression driven by endogenous regulatory elements.
Federica Pilotto, Laure Dall'Agnol, L. Reutenauer et al.· Human Gene Therapy· 0 citations
A lysosome-centered framework for understanding PGRN-related neurodegenerative pathologies is presented, and TMEM106B is discussed as a critical genetic modifier within this lysosomal network, highlighting its role in shaping disease risk and phenotypic heterogeneity.
Parkinson’s disease (PD) is the second most prevalent neurodegenerative disorder worldwide, characterized by progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the pathological accumulation of Lewy bodies composed predominantly of aggregated α-synuclein (αSyn). Despite decades of progress in genetics and neuropathology, the mechanisms driving disease initiation and progression remain incompletely understood, and no disease-modifying therapy has yet demonstrated conclusive efficacy. Neuroinflammation and metabolic dysfunction have emerged as two central and mechanistically intertwined pillars of PD pathogenesis. We propose an integrative model in which these processes function not merely in parallel, but as mutually reinforcing components of a self-amplifying pathological circuit, while acknowledging that this model remains to be fully validated and that alternative causal architectures are possible. This review systematically addresses the mechanistic coupling between neuroinflammation and metabolic dysregulation in PD, covering: (1) the molecular basis of innate immune activation via DAMPs, pattern recognition receptors, and inflammasome signaling; (2) microglial metabolic reprogramming and the NLRP3/NF-κB inflammatory axis; (3) αSyn-driven innate and adaptive immune responses; (4) mitochondrial dysfunction and oxidative stress as bidirectional amplifiers; (5) the gut-brain axis as a conduit for peripheral immunometabolic disruption; (6) the AMPK/mTOR/HIF-1α molecular network integrating metabolism and inflammation; (7) sphingolipid metabolism and the GBA-lysosomal axis; and (8) translational evidence from animal models and randomized controlled trials. A concise section integrates key fluid biomarkers as clinical surrogates of the underlying mechanisms.
Yi-Xin Fu, Jiang-Hao Yu, Lu Xu et al.· Frontiers in Immunology· 0 citations
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