Neuronal network dysfunction precedes storage and neurodegeneration in a lysosomal storage disorder

Ahrens‐Nicklas, Rebecca C.; Tecedor, Luis; Hall, Arron F; Лысенко, Елена; Cohen, Akiva S.; Davidson, Beverly L.; Marsh, Eric D.

doi:10.1172/jci.insight.131961

Cited by 19 publications

(26 citation statements)

References 57 publications

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“…Twelve-month-old Cln3 ∆ex78/∆ex78 mice have increased spike burden and a shift in background activity towards faster frequencies as compared to Cln3 ∆ex78/WT controls (Figure 1C-D). Specifically, there is decreased power in the slow delta frequency band (0.1-4Hz) and a trend towards increased power in the faster beta (13-25Hz) and gamma (25-50Hz) bands in Cln3 ∆ex78/∆ex78 mice, consistent with our previous report on Cln3 knock-out mice (12). Remarkably, restoring gene expression at p0 normalized spiking rates (Figure 1C) and corrected background activity (Figure 1D) in 12-monthold Cln3 ∆ex78/∆ex78 AAV9.CLN3-treated animals.…”

Section: Resultssupporting

confidence: 92%

“…Previously, we described network-level neurologic defects in two CLN3 disease mouse models using in vitro voltage sensitive dye imaging and in vivo electrophysiology techniques (12). We found that network-level changes begin early in the disease course before substantial storage accumulation.…”

Section: Introductionmentioning

confidence: 75%

“…In prior work, we found that CLN3 disease mouse models demonstrate robust, progressive neuronal network defects (12). We first assessed if neonatal correction of most CNS cell types could prevent circuit-level functional pathology.…”

Section: Resultsmentioning

confidence: 99%

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Neuronal genetic rescue normalizes brain network dynamics in a lysosomal storage disorder despite persistent storage accumulation

Tecedor

et al. 2021

Preprint

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Although neurologic symptoms occur in two-thirds of lysosomal storage disorders (LSDs), for most we do not understand the mechanisms underlying brain dysfunction. A major unanswered question is if the pathogenic hallmark of LSDs, storage accumulation, induces functional defects directly or is a disease bystander. Also, for most LSDs we do not know the impact of loss-of-function in individual cell types. Understanding these critical questions are essential to therapy development. Here, we determined the impact of genetic rescue in distinct cell types on neural circuit dysfunction in CLN3 disease, the most common pediatric dementia and a representative LSD. We restored Cln3 expression via AAV-mediated gene delivery and conditional genetic rescue in a CLN3 mouse model. Surprisingly, we found that low-level rescue of Cln3 expression in neurons alone normalized clinically-relevant electrophysiologic markers of network dysfunction, despite the presence of substantial residual histopathology, in contrast to restoring expression in astrocytes. Thus loss of Cln3 function in neurons, not storage accumulation, underlies neurologic dysfunction in CLN3 disease, implying that storage clearance may be an inappropriate target for therapy development and an ineffectual biomarker.

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Section: Resultssupporting

confidence: 92%

Section: Introductionmentioning

confidence: 75%

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Neuronal genetic rescue normalizes brain network dynamics in a lysosomal storage disorder despite persistent storage accumulation

Tecedor

et al. 2021

Preprint

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“…The authors propose that the two affected brain regions mediate different behavioural impairments with a common signature of a GABAergic deficit [125]. At the network level, a significant decrease in short wave ripples in the hippocampus (a characteristic oscillation often implicated in memory consolidation) over the course of the disease was found in a CLN3 mouse model (Cln3 -/-) suggesting that neuronal network defects in conjunction with synaptic deficits aggravate with age [126].…”

Section: Functional Synaptic Defectsmentioning

confidence: 99%

Neuropathophysiology of Lysosomal Storage Diseases: Synaptic Dysfunction as a Starting Point for Disease Progression

Pará

Bose

Pshezhetsky

2020

JCM

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About two thirds of the patients affected with lysosomal storage diseases (LSD) experience neurological manifestations, such as developmental delay, seizures, or psychiatric problems. In order to develop efficient therapies, it is crucial to understand the neuropathophysiology underlying these symptoms. How exactly lysosomal storage affects biogenesis and function of neurons is still under investigation however recent research highlights a substantial role played by synaptic defects, such as alterations in synaptic spines, synaptic proteins, postsynaptic densities, and synaptic vesicles that might lead to functional impairments in synaptic transmission and neurodegeneration, finally culminating in massive neuronal death and manifestation of cognitive symptoms. Unveiling how the synaptic components are affected in neurological LSD will thus enable a better understanding of the complexity of disease progression as well as identify crucial targets of therapeutic relevance and optimal time windows for targeted intervention.

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“…Each of these diseases is caused by a deficiency in a particular lysosomal protein or non-lysosomal protein associated with lysosomal biogenesis [ 19 ]. The accumulation of lysosomal cargoes and subsequent neurodegeneration are hallmarks of LSDs that influence cerebral functions [ 20 ]. To date, emphasis has been placed on the genetic sources of LSDs.…”

Section: Introductionmentioning

confidence: 99%

Ischemia-induced upregulation of autophagy preludes dysfunctional lysosomal storage and associated synaptic impairments in neurons

et al. 2020

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Neuronal network dysfunction precedes storage and neurodegeneration in a lysosomal storage disorder

Cited by 19 publications

References 57 publications

Neuronal genetic rescue normalizes brain network dynamics in a lysosomal storage disorder despite persistent storage accumulation

Neuronal genetic rescue normalizes brain network dynamics in a lysosomal storage disorder despite persistent storage accumulation

Neuropathophysiology of Lysosomal Storage Diseases: Synaptic Dysfunction as a Starting Point for Disease Progression

Ischemia-induced upregulation of autophagy preludes dysfunctional lysosomal storage and associated synaptic impairments in neurons

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