Selective Vulnerability of Layer 5a Corticostriatal Neurons in Huntington’s Disease

Pressl, Christina; Mätlik, Kert; Kus, Laura; Darnell, Paul; Luo, Ji‐Dung; Weiss, Alison R.; Liguore, William A.; Carroll, Thomas; Da, Davis; McBride, Jodi L.

doi:10.1101/2023.04.24.538096

Cited by 5 publications

(3 citation statements)

References 110 publications

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“…2E). Subcortical projection neurons are particularly vulnerable in HD, and transduction of these cells therefore makes AAV-DB-3 a particularly attractive capsid variant for HD gene therapies 21 . As further confirmation of cortical transduction, we also observed abundant AAV-DB-3.mTFP1 signal in axons within the internal capsule (Fig 2D).…”

Section: Resultsmentioning

confidence: 99%

“…To overcome the challenges for AAV gene therapies for disorders that impact cortical and subcortical structures like HD 21, 29 , we devised an unbiased approach to identify highly potent capsids capable of transducing our target brain regions following delivery to the globus pallidus. Our libraries were based on varying AAV serotypes, required only several animals for lead selection, and the resulting capsids did not require further optimization to improve their trafficking and targeting capabilities.…”

Section: Introductionmentioning

confidence: 99%

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Optimized AAV capsids for diseases of the basal ganglia show robust potency and distribution in adult nonhuman primates

Leib,

Chen,

Tecedor

et al. 2024

Preprint

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Huntington's disease and other disorders of the basal ganglia create challenges for biomolecule-based medicines given the poor accessibility of these deep brain structures following intracerebral or intravascular delivery. Additionally, for adeno-associated viruses (AAVs) intravascular delivery exposes peripheral tissues to the vast majority of the therapy, increasing the risk of immune responses and the quantity and associated cost of goods required for therapeutically relevant brain penetration levels. Here, we found that low dose, low volume delivery of unbiased AAV libraries into a focused brain region allowed recovery of novel capsids capable of broad access to key deep brain and cortical structures relevant for human therapies at doses orders of magnitude lower than used in current clinical trials. One such capsid, AAV-DB-3, provided transduction of up to 45% of medium spiny neurons in the adult NHP striatum, along with substantial transduction of relevant deep layer neurons in the cortex. Notably, AAV-DB-3 behaved similarly in mice as in NHPs and also potently transduced human neurons derived from induced pluripotent stem cells. Thus, AAV-DB-3 provides a unique AAV for network level brain gene therapies that translates up and down the evolutionary scale for preclinical studies and eventual clinical use.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Optimized AAV capsids for diseases of the basal ganglia show robust potency and distribution in adult nonhuman primates

Leib,

Chen,

Tecedor

et al. 2024

Preprint

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show abstract

“… 11–16 Moreover, analysis of post-mortem HD brains has shown that there is transcriptional dysregulation and somatic instability of the HTT CAG repeat in cortical neurons from HD expansion carriers. 17 However, a recent study including children and adolescents using a region of interest (ROI) approach, did not find significant differences in cortical thickness between HD expansion carriers and controls, 18 perhaps suggesting that these develop during early adulthood. 19 …”

Section: Introductionmentioning

confidence: 99%

Genetic topography and cortical cell loss in Huntington's disease link development and neurodegeneration

Estevez-Fraga,

Altmann,

Parker

et al. 2023

Brain

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Cortical cell loss is a core feature of Huntington Disease (HD), beginning many years before clinical motor diagnosis, during the premanifest stage. However, it is unclear how genetic topography relates to cortical cell loss. Here, we explore the biological processes and cell types underlying this relationship and validate this using cell-specific post-mortem data. Eighty premanifest participants on average 15 years from disease onset and 71 controls were included. Using volumetric and diffusion MRI we extracted HD-specific whole brain maps where lower grey matter volume and higher grey matter mean diffusivity, relative to controls, were used as proxies of cortical cell loss. These maps were combined with gene expression data from the Allen Human Brain Atlas (AHBA) to investigate the biological processes relating genetic topography and cortical cell loss. Cortical cell loss was positively correlated with the expression of developmental genes (i.e. higher expression correlated with greater atrophy and increased diffusivity) and negatively correlated with the expression of synaptic and metabolic genes that have been implicated in neurodegeneration. These findings were consistent for diffusion MRI and volumetric HD-specific brain maps. As wild type Huntingtin is known to play a role in neurodevelopment, we explored the association between wild type Huntingtin (HTT) expression and developmental gene expression across the AHBA. Co-expression network analyses in 134 human brains free of neurodegenerative disorders was also performed. HTT expression was correlated with the expression of genes involved in neurodevelopment while co-expression network analyses also revealed that HTT expression was associated with developmental biological processes. Expression weighted cell-type enrichment (EWCE) analyses were used to explore which specific cell-types were associated with HD cortical cell loss and these associations were validated using cell specific single nucleus RNAseq (snRNAseq) data from post-mortem HD brains. The developmental transcriptomic profile of cortical cell loss in preHD was enriched in astrocytes and endothelial cells, while the neurodegenerative transcriptomic profile was enriched for neuronal and microglial cells. Astrocyte-specific genes differentially expressed in HD post-mortem brains relative to controls using snRNAseq were enriched in the developmental transcriptomic profile, while neuronal and microglial-specific genes were enriched in the neurodegenerative transcriptomic profile Our findings suggest that cortical cell loss in preHD may arise from dual pathological processes, emerging as a consequence of neurodevelopmental changes, at the beginning of life, followed by neurodegeneration in adulthood, targeting areas with reduced expression of synaptic and metabolic genes. These events result in age-related cell death across multiple brain cell types.

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Cell-type-specific CAG repeat expansions and toxicity of mutant Huntingtin in human striatum and cerebellum

Mätlik,

Baffuto,

Kus

et al. 2024

Nat Genet

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Brain region-specific degeneration and somatic expansions of the mutant Huntingtin (mHTT) CAG tract are key features of Huntington’s disease (HD). However, the relationships among CAG expansions, death of specific cell types and molecular events associated with these processes are not established. Here, we used fluorescence-activated nuclear sorting (FANS) and deep molecular profiling to gain insight into the properties of cell types of the human striatum and cerebellum in HD and control donors. CAG expansions arise at mHTT in striatal medium spiny neurons (MSNs), cholinergic interneurons and cerebellar Purkinje neurons, and at mutant ATXN3 in MSNs from SCA3 donors. CAG expansions in MSNs are associated with higher levels of MSH2 and MSH3 (forming MutSβ), which can inhibit nucleolytic excision of CAG slip-outs by FAN1. Our data support a model in which CAG expansions are necessary but may not be sufficient for cell death and identify transcriptional changes associated with somatic CAG expansions and striatal toxicity.

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Selective Vulnerability of Layer 5a Corticostriatal Neurons in Huntington’s Disease

Cited by 5 publications

References 110 publications

Optimized AAV capsids for diseases of the basal ganglia show robust potency and distribution in adult nonhuman primates

Optimized AAV capsids for diseases of the basal ganglia show robust potency and distribution in adult nonhuman primates

Genetic topography and cortical cell loss in Huntington's disease link development and neurodegeneration

Cell-type-specific CAG repeat expansions and toxicity of mutant Huntingtin in human striatum and cerebellum

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