Aug 2026· Genes· Vol 17, pp. 965· 0 citations· 119 references
Medicine
TL;DR
It is argued that GBA1 loss-of-function and the resulting accumulation of glucosylceramide stabilise specific neurotoxic α-synuclein proteoforms, including soluble oligomers and self-templating conformational strains bearing defined post-translational modifications, and identifies the synapse as the most tractable node for early, disease-modifying intervention.
Abstract
Dementia with Lewy bodies (DLB) is increasingly conceptualised not merely as a disorder of neuronal death but as a primary synaptopathy in which the functional collapse of synaptic transmission and plasticity precedes, and predicts, neurodegeneration and clinical decline. Two genetic determinants dominate the heritable risk architecture of DLB: the α-synuclein gene SNCA, in which both copy-number variation and missense mutations exert dose- and conformation-dependent effects, and GBA1, encoding the lysosomal hydrolase glucocerebrosidase (GCase), the single most influential genetic risk factor for the disease. Here we synthesise evidence that these loci converge on a shared pathogenic endpoint—the impairment of activity-dependent synaptic plasticity. We argue that GBA1 loss-of-function and the resulting accumulation of glucosylceramide stabilise specific neurotoxic α-synuclein proteoforms, including soluble oligomers and self-templating conformational strains bearing defined post-translational modifications. These proteoforms are trafficked to, and enriched within, presynaptic terminals, where they disrupt SNARE-complex assembly and synaptic-vesicle dynamics, while postsynaptically they perturb NMDA and AMPA receptor trafficking, dysregulate dendritic calcium, and compromise synaptic mitochondrial bioenergetics. The net consequence is a metaplastic shift away from long-term potentiation (LTP) and toward aberrant long-term depression (LTD), a signature of synaptic failure detectable before frank pathology. We map these molecular events onto disease-relevant circuits—particularly the cholinergic basal forebrain and hippocampal–cortical and thalamocortical networks—and relate them to the defining neuropsychiatric features of DLB, including cognitive fluctuations and recurrent visual hallucinations. Finally, we evaluate emerging therapeutic strategies that target the GBA1–α-synuclein axis and that aim to restore synaptic plasticity directly. Positioning DLB within the framework of genetically determined plasticity deficits clarifies its kinship with other neuropsychiatric disorders and identifies the synapse as the most tractable node for early, disease-modifying intervention. We further examine how GBA1 allele severity and zygosity grade the phenotype, which genetic and environmental factors modify penetrance in carriers, and what distinguishes this synaptopathy from those driven by PSEN1/PSEN2, MAPT, or HTT, and we summarise the therapeutic pipeline—including enzyme augmentation and adeno-associated viral GBA1 gene therapy—that targets it.
Progranulin-related frontotemporal dementia (
GRN
-FTD) is an inherited neurodegenerative disorder caused by progranulin (PGRN) deficiency. Although PGRN functions are well characterized and several therapeutic strategies aiming to restore its levels are currently under evaluation, the mechanisms linking PGRN loss to neurodegeneration remain unclear. Exploiting a
Grn
knockout mouse model, we first investigated the impact of PGRN deficiency on behaviour longitudinally (4, 6, 9, and 12 months), then, at 12 months of age, the final time point assessed, we examined glucocerebrosidase (GCase) activity and consequent glucosylsphingosine (GS) accumulation, neuroinflammation, and molecular/morphological alterations at glutamatergic synapses.
Grn
-mutant mice displayed genotype-specific, age-dependent impairments in pheromone perception, memory deficits, and increased aggression. Reduced GCase activity and GS accumulation confirmed lysosomal dysfunction, which was associated with brain-region-specific alterations in AMPA- and NMDA-type glutamate receptor levels and reduced dendritic spine density, the latter observed only in
Grn
+/−
mice. These findings identify PGRN-related lysosomal dysfunction as a contributing factor to circuit disruption and behavioural deficits, highlighting the need for combinatorial therapeutic strategies going beyond PGRN replacement.
Chiara Bertasini, Maria Italia, Shima Tavakolian Haghighi et al.· Acta Neuropathologica Commun...· 0 citations
The SNCA gene on chromosome 4 encodes the alpha-synuclein (αSyn) protein, which plays a central role in the pathogenesis of synucleinopathies, including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). While αSyn has established roles in synaptic vesicle dynamics and neuronal signaling, alterations in SNCA regulation and sequence contribute to protein misfolding, aggregation, and loss of function. Alterations in secondary and tertiary structure, as well as protein aggregation, affect biochemical interactions, ultimately leading to pathogenesis. This review outlines the molecular architecture of the SNCA gene, including regulatory regions, alternative splicing, and untranslated regions that influence αSyn expression and isoform diversity. Seven missense mutations of the SNCA gene are discussed in detail from the genomic level, extending to phenotypic presentations. These missense mutations have different effects on the aggregation kinetics and fibril formation. Specific genotype-phenotype correlations are evident, with mutations such as A30P and H50Q commonly resembling idiopathic PD, E46K strongly associated with DLB, and G51D, A53T, and A53E linked to atypical parkinsonism and MSA-like syndromes. Differences in age at onset, disease progression, cognitive involvement, and response to therapy further reflect mutation-specific effects and modifying influences of allelic dosage and epigenetic regulation. Collectively, these findings emphasize the importance of SNCA genetic variation in shaping disease phenotype and progression. Improving the understanding of SNCA genotype-phenotype relationships in future studies may facilitate earlier diagnosis, refine prognostic stratification, and support the development of targeted, disease-modifying therapies for synucleinopathies.
Pranaya Gade, Nishant Patel, J. P. Rissardo et al.· Molecular and cellular neuro...· 0 citations
Lewy body dementia (LBD), encompassing Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB), is defined by widespread α-synuclein (αSyn) aggregation and frequently exhibits coexistent tau and amyloid-β (Aβ) pathologies. However, whether αSyn pathology is sufficient to drive endogenous tau and Aβ aggregation has remained unclear due to a lack of in vivo models that recapitulate the full spectrum of LBD-associated proteinopathies and neurodegeneration. AIMP2, a parkin substrate that accumulates in Parkinson’s disease, enhances αSyn aggregation and toxicity, but its role in initiating downstream mixed pathologies across vulnerable brain regions has not been demonstrated in vivo. Here, we generated a conditional, neuron-specific Tet-Off double-transgenic mouse model enabling post-developmental coexpression of AIMP2 and A53T αSyn. This synergistic coexpression induced rapid and widespread αSyn aggregation, detergent-insoluble Lewy-like inclusions, mitochondrial degeneration, synaptic impairment, and neuronal loss, accompanied by marked gliosis. Mice developed key clinical features of LBD, including progressive cognitive impairment, bradykinesia, and olfactory deficits. Notably, without tau or APP overexpression, endogenous tau became hyperphosphorylated through dysregulated kinase signaling, and Aβ accumulated predominantly as TBS-soluble Aβ42 monomers/oligomers without fibrillar plaque deposition, demonstrating that AIMP2–αSyn–driven pathology is sufficient to trigger downstream tauopathy and Aβ pathologies. These mixed pathologies were associated with lysosomal and proteasomal dysfunction, evidenced by p62 and polyubiquitinated protein accumulation. Proteomic analysis identified dysregulation of pathways linked to amyloid processing, synaptic trafficking, and protein quality control. Importantly, temporal suppression of AIMP2 and αSyn expression promoted reduction of pre-existing pathologies and partially restored cognitive function. This study establishes a genetically controlled in vivo model of LBD-like mixed proteinopathy recapitulating αSyn aggregation, tau hyperphosphorylation, Aβ accumulation, neurodegeneration, and behavioral decline. These findings support a mechanistic link between AIMP2-enhanced αSyn toxicity and secondary proteinopathies and position this model as a platform for mechanistic and therapeutic studies in complex α-synucleinopathies.
Doeun Kim, Hee-Tae Kim, Ji Hun Kim et al.· Cell Death & Disease· 0 citations
Presenilins are best known as the catalytic core of γ-secretase, where familial Alzheimer's disease (FAD) mutations shift amyloid-β (Aβ) trimming toward aggregation-prone species. Yet conditional and cell-type-specific genetic analyses in mice now place presenilin (PS) biology far beyond amyloidogenesis. In PS1/PS2 conditional double-knockout (PS cDKO) models, where presenilins are inactivated postnatally in forebrain excitatory neurons, the earliest phenotype is a synaptopathy: presynaptic release probability and short-term plasticity collapse, N-methyl-D-aspartate receptor (NMDAR) function wanes, and cAMP response element-binding protein (CREB)/CREB-binding protein (CBP)-dependent transcriptional programs falter. Compensatory glial responses rapidly consolidate into a neuroinflammatory state, with inflammasome activation and cytokine surges that further erode synaptic signaling and promote tau hyperphosphorylation. Progressive cortical and callosal atrophy and ventriculomegaly follow, culminating in neuron loss, even as cortical Aβ is reduced, severing the mechanistic necessity of plaques for degeneration. Across interventions, anti-inflammatory, cholinergic, and metabolic manipulations rescue cognition and plasticity in PS cDKO mice without engaging amyloid, underscoring a disease axis that is Aβ-independent yet clinically salient. Here we synthesize lessons from PS cDKO studies, integrate them with contemporary presenilins/γ-secretase biology, and outline a translational agenda focused on presynaptic Ca2+ microdomains, RyR-coupled release, activity-dependent gene programs, and innate immune checkpoints. We conclude that PS integrate vesicular release machinery with trophic and inflammatory homeostasis; their loss initiates a multi-scale failure cascade that redefines early AD-related neurodegeneration beyond Aβ.
The Parkinson’s Vulnerability Index (PVI) is proposed, a hypothesis-generating multidimensional model combining genetic, enzymatic, alpha-synuclein seeding, cognitive, olfactory, and neuroimaging biomarkers to facilitate biological stratification and improve the design of mechanism-targeted clinical trials.
Livia Livinț-Popa, Andreea Nicolaie, A. Maștaleru et al.· Medical Science· 0 citations
Introduction Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized pathologically by the accumulation and propagation of α-synuclein (α-syn). Although α-syn aggregation is considered central to PD pathogenesis, increasing evidence suggests that α-syn abundance may be as important as its conformational state. Genetic studies have demonstrated an SNCA dosage effect, with gene duplication and triplication associated with progressively more severe familial PD phenotypes. Complementary evidence indicates that dysfunction of protein clearance pathways, particularly the autophagy–lysosome system, promotes intracellular α-syn accumulation and increases its neurotoxic potential. In this review, we propose α-syn multiplication as an integrative framework for interpreting PD pathogenesis. This concept extends beyond SNCA copy-number variation to encompass processes that increase the effective α-syn burden within neurons or across neural networks, including increased gene expression, impaired degradation, disrupted proteostasis, and pathological propagation. Methods We summarize α-syn structural dynamics and the concentration-dependent distribution of monomeric, oligomeric, and fibrillar species. We then review evidence from SNCA gene-dosage studies and examine the role of the autophagy–lysosome pathway in regulating α-syn homeostasis, with particular emphasis on recent experimental findings demonstrating that autophagy deficiency exacerbates α-syn accumulation and neurodegeneration in human α-syn bacterial artificial chromosome transgenic mice. Results Collectively, the available genetic, biochemical, and experimental evidence supports a model in which the balance between α-syn production and clearance influences disease progression alongside protein misfolding. The interaction between increased protein burden and impaired clearance capacity provides a unifying mechanism linking familial and sporadic forms of PD. Discussion We propose that α-syn multiplication offers an integrative framework for understanding PD pathogenesis, provides a quantitative perspective on disease heterogeneity, and highlights therapeutic opportunities aimed at reducing α-syn burden and restoring proteostatic balance.
Sachiko Noda, Nobutaka Hattori· Frontiers in Neurology· 0 citations
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