AAV-based gene therapy approaches for genetic forms of tauopathies and related neurogenetic disorders

KABBANI, MOHAMED AGHYAD AL; Wunderlich, Gilbert; K鯤LER, CHRISTOPH; Zempel, Hans

doi:10.32604/biocell.2022.018144

Cited by 3 publications

(3 citation statements)

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“…be induced by specific human disease-associated substances (e.g. AD-specific Amyloid-beta oligomers), but also neuron-specific (via excitotoxic stressors such as glutamate) or general cellular stress (elevated calcium, reactive oxygen species) (Zempel et al 2010 ), and by dysregulation of the Tau kinase MARK (Chudobová and Zempel 2023 ), and can be observed in a number of genetic and non-genetic tauopathies (Zimmer-Bensch and Zempel 2021 ; Al Kabbani et al 2022 ). For the exception of very rare genetic forms of tauopathies (like frontotemporal dementia due to mutation in the gene MAPT ), Tau somatic accumulation is a consequence.…”

Section: Discussionmentioning

confidence: 99%

Laser-Induced Axotomy of Human iPSC-Derived and Murine Primary Neurons Decreases Somatic Tau and AT8 Tau Phosphorylation: A Single-Cell Approach to Study Effects of Acute Axonal Damage

et al. 2023

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The microtubule-associated protein Tau is highly enriched in axons of brain neurons where it regulates axonal outgrowth, plasticity, and transport. Efficient axonal Tau sorting is critical since somatodendritic Tau missorting is a major hallmark of Alzheimer’s disease and other tauopathies. However, the molecular mechanisms of axonal Tau sorting are still not fully understood. In this study, we aimed to unravel to which extent anterograde protein transport contributes to axonal Tau sorting. We developed a laser-based axotomy approach with single-cell resolution and combined it with spinning disk confocal microscopy enabling multi live-cell monitoring. We cultivated human iPSC-derived cortical neurons and mouse primary forebrain neurons in specialized chambers allowing reliable post-fixation identification and Tau analysis. Using this approach, we achieved high post-axotomy survival rates and observed axonal regrowth in a subset of neurons. When we assessed somatic missorting and phosphorylation levels of endogenous human or murine Tau at different time points after axotomy, we surprisingly did not observe somatic Tau accumulation or hyperphosphorylation, regardless of their regrowing activity, consistent for both models. These results indicate that impairment of anterograde transit of Tau protein and acute axonal damage may not play a role for the development of somatic Tau pathology. In sum, we developed a laser-based axotomy model suitable for studying the impact of different Tau sorting mechanisms in a highly controllable and reproducible setting, and we provide evidence that acute axon loss does not induce somatic Tau accumulation and AT8 Tau phosphorylation. Graphical Abstract UV laser-induced axotomy of human iPSC-derived and mouse primary neurons results in decreased somatic levels of endogenous Tau and AT8 Tau phosphorylation.

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Section: Discussionmentioning

confidence: 99%

Laser-Induced Axotomy of Human iPSC-Derived and Murine Primary Neurons Decreases Somatic Tau and AT8 Tau Phosphorylation: A Single-Cell Approach to Study Effects of Acute Axonal Damage

et al. 2023

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“…While TAU-based therapeutic strategies are certainly valid (see e.g. Al Kabbani et al [ 132 ]), more insights in the future will help to develop better biomarkers to differentially diagnose and monitor these diseases, and will unveil more specific and genetically validated therapeutic targets.…”

Section: Secondary Tauopathiesmentioning

confidence: 99%

Genetic forms of tauopathies: inherited causes and implications of Alzheimer’s disease-like TAU pathology in primary and secondary tauopathies

Langerscheidt,

Wied,

Al Kabbani

et al. 2024

J Neurol

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Tauopathies are a heterogeneous group of neurologic diseases characterized by pathological axodendritic distribution, ectopic expression, and/or phosphorylation and aggregation of the microtubule-associated protein TAU, encoded by the gene MAPT. Neuronal dysfunction, dementia, and neurodegeneration are common features of these often detrimental diseases. A neurodegenerative disease is considered a primary tauopathy when MAPT mutations/haplotypes are its primary cause and/or TAU is the main pathological feature. In case TAU pathology is observed but superimposed by another pathological hallmark, the condition is classified as a secondary tauopathy. In some tauopathies (e.g. MAPT-associated frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and Alzheimer's disease (AD)) TAU is recognized as a significant pathogenic driver of the disease. In many secondary tauopathies, including Parkinson's disease (PD) and Huntington's disease (HD), TAU is suggested to contribute to the development of dementia, but in others (e.g. Niemann-Pick disease (NPC)) TAU may only be a bystander. The genetic and pathological mechanisms underlying TAU pathology are often not fully understood. In this review, the genetic predispositions and variants associated with both primary and secondary tauopathies are examined in detail, assessing evidence for the role of TAU in these conditions. We highlight less common genetic forms of tauopathies to increase awareness for these disorders and the involvement of TAU in their pathology. This approach not only contributes to a deeper understanding of these conditions but may also lay the groundwork for potential TAU-based therapeutic interventions for various tauopathies.

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“…We now include (i) tauopathies where the disease cause or trigger is clearly either physical, such as in Traumatic Brain Injury (TBI) or Chronic Traumatic Encephalopathy (CTE), and (ii) also genetic diseases that result in tauopathy but have pathogenic genetic variants in genes not related to TAU. Examples are Myotonic Dystrophie (DM) Type 1 or Type 2 (due to pathogenic genetic variants in the genes DMPK and CNBP , respectively), Niemann–Pick Disease Type C (NPD, due to mutations in NPC1 or NPC2 ), Kufs Disease ( CLN6 ), Christianson Syndrome ( SLC9A6 ), familial forms of Parkinson Disease (PD) and many others (reviewed in (Al Kabbani et al, 2022; Ali & Josephs, 2019; Guo et al, 2017; Mulroy et al, 2020; Tacik, Sanchez‐Contreras, et al, 2016; Tacik, Wszolek, et al, 2016; Zimmer‐Bensch & Zempel, 2021)).…”

Section: Figurementioning

confidence: 99%

Genetic and sporadic forms of tauopathies—TAU as a disease driver for the majority of patients but the minority of tauopathies

Zempel

2023

Cytoskeleton

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Ageing‐associated tauopathies like frontotemporal dementia (FTD), variants thereof (like progressive supranuclear palsy (PSP), pick diseases (PiD), corticobasal degeneration (CBD)), and of course the most prevalent form of dementia, Alzheimer Disease (AD), are widely recognized forms of tauopathies. The list of tauopathies is expanding. We now include: (i) tauopathies where the disease cause or trigger is clearly either physical, such as in Traumatic Brain Injury (TBI) or Chronic Traumatic Encephalopathy (CTE), and (ii) genetic diseases that result in tauopathy but have pathogenic genetic variants in genes not related to TAU. Examples of the latter are myotonic dystrophy Type 1 and Type 2 (DM1, DM2, due to pathogenic genetic variants in the genes DMPK and CNBP, respectively), Niemann–Pick Disease Type C (NPD, due to mutations in NPC1 or NPC2), Kufs Disease (CLN6), Christianson Syndrome (SLC9A6), familial forms of Parkinson Disease (PD), and many others. In terms of affected brain regions and cell types, intracellular distribution of TAU pathology/aggregates, age of disease onset, velocity of disease progression and spreading of TAU pathology, there is, however, little in common in most of these disease entities. Here, I reason that TAU/MAPT is causative for the minority of tauopathies (e.g., MAPT‐related FTD/PSP and Vacuolar Tauopathy (VCP)) and a critical mediator for others, like shown by overwhelming evidence for AD. However, TAU may also be a mere bystander or even protective in other settings. Improved understanding of rare tauopathies is necessary to develop specific treatments, but also to improve our understanding of the pathomechanistic role of TAU and to identify diseases that may profit from TAU‐based therapies.

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AAV-based gene therapy approaches for genetic forms of tauopathies and related neurogenetic disorders

Cited by 3 publications

References 41 publications

Laser-Induced Axotomy of Human iPSC-Derived and Murine Primary Neurons Decreases Somatic Tau and AT8 Tau Phosphorylation: A Single-Cell Approach to Study Effects of Acute Axonal Damage

Laser-Induced Axotomy of Human iPSC-Derived and Murine Primary Neurons Decreases Somatic Tau and AT8 Tau Phosphorylation: A Single-Cell Approach to Study Effects of Acute Axonal Damage

Genetic forms of tauopathies: inherited causes and implications of Alzheimer’s disease-like TAU pathology in primary and secondary tauopathies

Genetic and sporadic forms of tauopathies—TAU as a disease driver for the majority of patients but the minority of tauopathies

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