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Top-down and bottom-up propagation of disease in the neuronal ceroid lipofuscinoses.



Ostergaard, John R;

Nelvagal, Hemanth R;

Cooper, Jonathan D;

(2022)

Top-down and bottom-up propagation of disease in the neuronal ceroid lipofuscinoses.

Frontiers in Neurology
, 13


, Article 1061363. 10.3389/fneur.2022.1061363.

Abstract

BACKGROUND: The Neuronal Ceroid Lipofuscinoses (NCLs) may be considered distinct neurodegenerative disorders with separate underlying molecular causes resulting from monogenetic mutations. An alternative hypothesis is to consider the NCLs as related diseases that share lipofuscin pathobiology as the common core feature, but otherwise distinguished by different a) initial anatomic location, and b) disease propagation. METHODS: We have tested this hypothesis by comparing known differences in symptomatology and pathology of the CLN1 phenotype caused by complete loss of PPT1 function (i.e., the classical infantile form) and of the classical juvenile CLN3 phenotype. These two forms of NCL represent early onset and rapidly progressing vs. late onset and slowly progressing disease modalities respectively. RESULTS: Despite displaying similar pathological endpoints, the clinical phenotypes and the evidence of imaging and postmortem studies reveal strikingly different time courses and distributions of disease propagation. Data from CLN1 disease are indicative of disease propagation from the body, with early effects within the spinal cord and subsequently within the brainstem, the cerebral hemispheres, cerebellum and retina. In contrast, the retina appears to be the most vulnerable organ in CLN3, and the site where pathology is first present. Pathology subsequently is present in the occipital connectome of the CLN3 brain, followed by a top-down propagation in which cerebral and cerebellar atrophy in early adolescence is followed by involvement of the peripheral nerves in later adolescence/early twenties, with the extrapyramidal system also affected during this time course. DISCUSSION: The propagation of disease in these two NCLs therefore has much in common with the “Brain-first” vs. “Body-first” models of alpha-synuclein propagation in Parkinson’s disease. CLN1 disease represents a “Body-first” or bottom-up disease propagation and CLN3 disease having a “Brain-first” and top-down propagation. It is noteworthy that the varied phenotypes of CLN1 disease, whether it starts in infancy (infantile form) or later in childhood (juvenile form), still fit with our proposed hypothesis of a bottom-up disease propagation in CLN1. Likewise, in protracted CLN3 disease, where both cognitive and motor declines are delayed, the initial manifestations of disease are also seen in the outer retinal layers, i.e., identical to classical Juvenile NCL disease.

Type: Article

Title: Top-down and bottom-up propagation of disease in the neuronal ceroid lipofuscinoses.
Location: Switzerland
Open access status: An open access version is available from UCL Discovery
DOI: 10.3389/fneur.2022.1061363
Publisher version: https://doi.org/10.3389/fneur.2022.1061363
Language: English
Additional information: © 2022 Ostergaard, Nelvagal and Cooper. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Keywords: Body-first, Brain-first, CLN1, CLN3, connectome, disease propagation, neurodegeneration, neuronal ceroid lipofuscinoses
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Pharmacology
URI: https://discovery.ucl.ac.uk/id/eprint/10161216
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