Acta Neuropathologica最新文献

Charcot–Marie–Tooth disease type 2Z (CMT2Z) is an inherited axonal neuropathy caused by haploinsufficiency of microrchidia CW-type zinc finger protein 2 (MORC2), which leads to elevated hydroxyl radical levels, reduced ATPase activity, and apoptosis-mediated neuromuscular degeneration. CMT2Z presents with severe clinical manifestations, yet no widely applicable and affordable treatment has been developed. While gene therapy presents a theoretical solution, its feasibility remains constrained by prohibitive costs and delivery challenges. We observed sex-specific differences in muscle function in a CMT2Z mouse model carrying the microrchidia CW-type zinc finger protein 2A (Morc2a) p.S87L variant, with males exhibiting more severe weakness, suggesting a protective role of estradiol in females. Thus, we hypothesized that identifying and utilizing this factor could contribute to CMT2Z drug development. We found that estradiol stabilizes the Morc2a variant protein by inhibiting autophagy, independently of specific estrogen receptors, thereby mitigating hydroxyl radical–induced mitochondrial aggregation and apoptosis while restoring ATPase function. Subcutaneous implantation of estradiol pellets in the CMT2Z mouse model significantly improved Morc2a protein stability in the quadriceps femoris and sciatic nerve, reversed mitochondrial aggregation, and ameliorated both muscular and peripheral nerve degeneration. Notably, symptomatic Morc2a p.S87L mice exhibited robust peripheral nerve regeneration, demonstrating estradiol’s ability to restore function rather than merely delay disease progression. Moreover, the therapeutic effects were reproduced in human MORC2 p.R252W variants, further confirming its translational potential. As an FDA-approved compound with well-characterized pharmacokinetics, estradiol represents a rapidly deployable strategy for treating CMT2Z. This study highlights the pivotal role of oxidative stress in the pathophysiology of CMT2Z and identifies MORC2 stabilization as a promising intervention. Moreover, the findings advocate for repurposing existing therapeutics to address rare genetic disorders, broadening treatment paradigms for neuromuscular diseases beyond CMT2Z.

CNS embryonal tumors with PLAGL amplification (ET, PLAGL) are a recently described tumor type marked by amplification of one of the PLAG family genes, PLAGL1 or PLAGL2. Separately, a supratentorial, ependymoma-like CNS tumor type with PLAG family alteration, namely PLAGL1 fusion, was also reported (NET_PLAGL1). Here, we use DNA methylation profiling in combination with copy number, RNA-seq, and histological analysis to characterize and classify a novel group of CNS embryonal tumors harboring PLAG1 gene fusions (n=12). Through our screening, we identified a subset of CNS tumors (n=12) epigenetically distinct from other known CNS tumor types, but clustering close to the PLAGL1- and PLAGL2-amplified ET, PLAGL subtypes in our t-SNE analysis. Copy number profiles indicated putative PLAG1 fusions, which were confirmed in 9/12 tumors (not determined in 3/12). Different 5’ fusion partners (ASAP1, ADGRG1, TMEM68, TCF4, CHD7, NCALD, HNRNPK, LOC105378102) were identified that upregulate wild-type PLAG1 through promoter hijacking. Expression analysis shows upregulation of PLAG1 as well as IGF2, DLK1, Desmin, CYP2W1, and RET, which are also robustly expressed in PLAGL1/2-amplified tumors. Patient characteristics, survival data, and clinical/imaging analysis show additional similarities to PLAGL1/2-amplified tumors. Median age at diagnosis was 5 years, tumors were located throughout the neuroaxis, and original histological diagnoses were heterogeneous. The tumors demonstrated morphologic heterogeneity, with most composed of densely cellular areas of primitive small blue cells, alongside focal regions showing clear cell morphology, microcystic changes, and ependymoma-like perivascular pseudorosettes. Applied treatment regimens were also heterogeneous, but some favorable responses to therapy were observed. In summary, we describe a third subtype of PLAG family-altered pediatric CNS embryonal tumor characterized by PLAG1 gene fusion, which leads to upregulation of PLAG1 and downstream genes. We therefore propose to rename ET, PLAGL to ET, PLAG (CNS embryonal tumor with PLAG family gene alteration) together with a specification of the respective subtype.

Cardiac manifestations are associated with Lewy body disease, but studies addressing the underlying histopathological mechanisms at the myocardial level are sparse. Here, we generated an artificial intelligence-based algorithm to quantify tyrosine hydroxylase (TH)-immunoreactive sympathetic distal axons at the myocardial level. This novel tool was applied to septal samples of the Vantaa 85 + study (n = 138), which is a population-based autopsy study representing all subjects aged 85 years or older living in the city of Vantaa (southern Finland) in 1991. In addition, the tool was applied to left ventricle samples of the Helsinki Biobank (n = 87) and the forensic Tampere Sudden Death Study (TSDS, n = 127). The level of myocardial TH reactivity was compared between subjects with and without Lewy pathology in the central nervous system in all datasets. In the Vantaa 85 + study, TH reactivity was also compared between subjects with caudo-rostral and amygdala-based subtypes, and potential confounding factors (age at death, sex, myocardial infarction, senile systemic amyloidosis, and diabetes medication) were controlled for using multiple linear regression models. Presence of Lewy pathology was strongly associated with loss of TH reactivity at the myocardial level in all three autopsy cohorts (Vantaa 85 + p = 0.001, Helsinki Biobank p < 0.001, TSDS p < 0.001)). In the Vantaa 85 + study, the caudo-rostral subtype (p < 0.001), but not the amygdala-based subtype (p = 0.60), was associated with myocardial denervation/dysfunction, and this association was independent of other known causes of sympathetic denervation/dysfunction. Caudo-rostral subtype and myocardial infarction were the strongest predictors of myocardial sympathetic denervation/dysfunction in the oldest-old population (Vantaa 85 +). In conclusion, our results show that Lewy pathology in the central nervous system, and particularly its caudo-rostral subtype, is strongly associated with loss of sympathetic distal axons at the myocardial level. We also provide evidence that the caudo-rostral subtype is one of the strongest predictors of myocardial sympathetic denervation/dysfunction in the oldest-old population.

Development of therapeutic approaches that target specific microglia responses in amyotrophic lateral sclerosis (ALS) is crucial due to the involvement of microglia in ALS progression. Our study identifies the predominant microglia subset in human ALS primary motor cortex and spinal cord as an undifferentiated phenotype with dysregulated respiratory electron transport. Moreover, we find that the interferon response microglia subset is enriched in donors with aggressive disease progression, while a previously described potentially protective microglia phenotype is depleted in ALS. Additionally, we observe an enrichment of non-microglial immune cell, mainly NK/T cells, in the ALS central nervous system, primarily in the spinal cord. These findings pave the way for the development of microglia subset-specific therapeutic interventions to slow or even stop ALS progression.

Primary age-related tauopathy (PART) has been associated with milder degrees of cognitive impairment, but the role of PART-related tangles, from the hippocampus, nearby inferior temporal neocortex, and the role of co-existing pathologies on cognitive decline are underappreciated. We used three harmonized community-based clinicopathologic studies to investigate the association of regional distributions of tangles and co-existing pathologies with cognitive decline. At autopsy, PART was defined by a Braak NFT stage of I–IV in the absence or with limited amyloid-β (Thal ≤ 2). Tau tangle density from the hippocampus and inferior temporal cortex were evaluated by AT8-immunohistochemistry. Other brain pathologies (LATE-NC, Lewy bodies (LBs), and vascular pathologies) were also evaluated. Linear mixed effect models were employed to examine the associations between regional tau tangles and other brain pathologies with decline in global cognition and 5 cognitive domains. Among 1,859 participants, 527 (28%) had neuropathologically confirmed PART: 385 had possible PART and 142 had definite PART, with an average age at death of 88 ± 6.9 years and 63% being female. Nearly all PART participants (N = 524) had hippocampal tangles and 449 also exhibited tangles in the inferior temporal neocortex. After controlling demographics and other brain pathologies, hippocampal and inferior temporal neocortical tangle burden were each associated with decline in global cognition and episodic memory; however, the effect of inferior temporal neocortical tangles on decline was 3.2 times stronger than that of hippocampal tangles. In further analyses, when included together in the same model, only the association of inferior temporal neocortical tangle burden persisted. However, using Braak staging alone, we did not find a clinical–pathological relationship between tangles and cognitive decline. Additionally, LATE-NC, LBs, atherosclerosis, and cerebral infarcts were each independently associated with cognitive decline. Our data also indicated that LATE-NC may have stronger impact on cognitive decline in PART than tau tangles. Overall, this study provides evidence that both extension of tangles to the nearby neocortex, specifically the inferior temporal, along with other co-pathologies, particularly LATE-NC, play a key role in cognitive decline in PART.

Extracellular amyloid plaques, the pathognomonic hallmark of Alzheimer’s disease (AD), are also observed in cognitively unimpaired subjects in the preclinical stages. Progressive accumulation of fibrillar amyloid-β (Aβ) as plaques and perivascular deposits occur two decades before clinical onset, making Aβ a long-lived peptide. To characterize the amyloid plaques biochemically, both the Aβ-load as well the post-translational modifications (PTMs) could serve as markers for distinguishing the pre-clinical stage compared to later prodromal and clinical stages of AD. Recently, we described the presence of extensive isomerization of the Aβ N-terminus in AD post-mortem brains that is significantly increased compared to the age-matched non-AD control brains with Aβ aggregates. In this report, we performed Lys-N enzymatic digestion followed by mass spectrometry-based quantitative analysis of the most common PTMs associated with plaque Aβ. We focused on pyroglutamation (pGlu3), citrullination (cit5), N-terminal truncation (Aβ_4-x), C-terminal isoforms (Aβ_x-42 and Aβ_x-40), and isomerization of aspartic acid residues (Asp-1 and Asp-7) in postmortem human brain tissue from pathologically negative (no Aβ plaques) controls (n = 23), controls with Aβ plaques (n = 35), Parkinson’s disease (PD) with (n = 28) and without Aβ accumulation/plaques (n = 30) and symptomatic AD (n = 60). The AD cases contained statistically significant amounts of Asp-1 and Asp-7 isomerized Aβ (~ 90%) compared to controls (preclinical AD) and PD brains with fibrillar Aβ aggregates/deposits. We find that the ratio of isomerized N-terminus Aβ (Aβ_1-x) species in the brain detergent soluble pool differentiates older fibrillar Aβ deposits in symptomatic AD brain compared to Aβ deposits detected in preclinical AD and PD. Citrullinated pGlu3-Aβ was increased only in symptomatic AD, highlighting this Aβ PTM is a unique feature of parenchymal plaques in advanced AD. Our results have implications for early therapeutic targeting of these modified species as well as potential for better biofluid biomarker development for drug efficacy monitoring.

ATP10B, a transmembrane lipid flippase located in late endosomes and lysosomes, facilitates the export of glucosylceramide and phosphatidylcholine by coupling this process to ATP hydrolysis. Recently, loss-of-function mutations in the ATP10B gene have been identified in Parkinson’s disease patients, pointing to ATP10B as a candidate genetic risk factor. Previous studies have shown compromised lysosomal functionality upon ATP10B knockdown in human cell lines and primary cortical neurons. To investigate the role of ATP10B in Parkinson’s disease neuropathology, specifically in the nigrostriatal dopaminergic system, we induced ATP10B knockdown specifically in substantia nigra pars compacta neurons of rats using viral vector technology. Additionally, midbrain neuronal cultures derived from ATP10B knock-out human induced pluripotent stem cells clones were used to study the impact of ATP10B loss in dopaminergic neurons in a more translational model. Atp10b knockdown in rat brain induced parkinsonian motor deficits, and longitudinal striatal dopamine transporter ¹⁸F-FE-PE2I PET imaging revealed a progressive decrease in binding potential. Immunohistochemical analysis conducted one year post-injection confirmed the loss of dopaminergic terminals in the striatum, alongside a loss of dopaminergic neurons in the substantia nigra pars compacta. The expression of LAMP1, LAMP2a, cathepsin B and glucocerebrosidase was studied in dopaminergic neurons. A decrease in lysosomal numbers and an increase in lysosomal volume were observed more consistently in one of the knockdown constructs. The vulnerability of dopaminergic neurons to ATP10B loss-of-function was also observed in midbrain neuronal cultures derived from ATP10B knock-out human induced pluripotent stem cells clones, which showed a significant reduction in TH-positive neurons. Taken together, our findings demonstrate that ATP10B depletion detrimentally impacts the viability of dopaminergic neurons both in vivo and in vitro. Moreover, a broader impact on the functionality of the nigrostriatal pathway was evidenced as rats with Atp10b knockdown exhibited motor impairments similar to those observed in Parkinson’s disease patients.