Dataset Information

Emerging new roles of the lysosome and neuronal ceroid lipofuscinoses.

ABSTRACT: Neuronal Ceroid Lipofuscinoses (NCLs), commonly known as Batten disease, constitute a group of the most prevalent neurodegenerative lysosomal storage disorders (LSDs). Mutations in at least 13 different genes (called CLNs) cause various forms of NCLs. Clinically, the NCLs manifest early impairment of vision, progressive decline in cognitive and motor functions, seizures and a shortened lifespan. At the cellular level, all NCLs show intracellular accumulation of autofluorescent material (called ceroid) and progressive neuron loss. Despite intense studies the normal physiological functions of each of the CLN genes remain poorly understood. Consequently, the development of mechanism-based therapeutic strategies remains challenging. Endolysosomal dysfunction contributes to pathogenesis of virtually all LSDs. Studies within the past decade have drastically changed the notion that the lysosomes are merely the terminal degradative organelles. The emerging new roles of the lysosome include its central role in nutrient-dependent signal transduction regulating metabolism and cellular proliferation or quiescence. In this review, we first provide a brief overview of the endolysosomal and autophagic pathways, lysosomal acidification and endosome-lysosome and autophagosome-lysosome fusions. We emphasize the importance of these processes as their dysregulation leads to pathogenesis of many LSDs including the NCLs. We also describe what is currently known about each of the 13 CLN genes and their products and how understanding the emerging new roles of the lysosome may clarify the underlying pathogenic mechanisms of the NCLs. Finally, we discuss the current and emerging therapeutic strategies for various NCLs.

SUBMITTER: Mukherjee AB

PROVIDER: S-EPMC6335712 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Emerging new roles of the lysosome and neuronal ceroid lipofuscinoses.

Mukherjee Anil B AB Appu Abhilash P AP Sadhukhan Tamal T Casey Sydney S Mondal Avisek A Zhang Zhongjian Z Bagh Maria B MB

Molecular neurodegeneration 20190116 1

Neuronal Ceroid Lipofuscinoses (NCLs), commonly known as Batten disease, constitute a group of the most prevalent neurodegenerative lysosomal storage disorders (LSDs). Mutations in at least 13 different genes (called CLNs) cause various forms of NCLs. Clinically, the NCLs manifest early impairment of vision, progressive decline in cognitive and motor functions, seizures and a shortened lifespan. At the cellular level, all NCLs show intracellular accumulation of autofluorescent material (called c ...[more]

PMID: 30651094

Similar Datasets

Project description:Background and purposeNeuronal ceroid lipofuscinoses are a group of neurodegenerative disorders characterized by the accumulation of autofluorescent lipopigments in neuronal cells. As a result of storage material in the brain and retina, clinical manifestations include speech delay, cognitive dysfunction, motor regression, epilepsy, vision loss, and early death. At present, 14 different ceroid lipofuscinosis (CLN) genes are known. Recently, the FDA approved the use of recombinant human proenzyme of tripeptidyl-peptidase 1 for CLN2 disease, while phase I/IIa clinical trials for gene therapy in CLN3 and CLN6 are ongoing. Early diagnosis is, therefore, key to initiating treatment and arresting disease progression. Neuroimaging features of CLN1, CLN2, CLN3, and CLN5 diseases are well-described, with sparse literature on other subtypes. We aimed to investigate and expand the MR imaging features of genetically proved neuronal ceroid lipofuscinoses subtypes at our institution and also to report the time interval between the age of disease onset and the diagnosis of neuronal ceroid lipofuscinoses.Materials and methodsWe investigated and analyzed the age of disease onset and neuroimaging findings (signal intensity in periventricular, deep, and subcortical white matter, thalami, basal ganglia, posterior limb of the internal capsule, insular/subinsular regions, and ventral pons; and the presence or absence of supratentorial and/or infratentorial atrophy) of patients with genetically proved neuronal ceroid lipofuscinoses at our institution. This group consisted of 24 patients who underwent 40 brain MR imaging investigations between 1993 and 2019, with a male preponderance (male/female ratio = 15:9).ResultsThe mean ages of disease onset, first brain MR imaging, and diagnosis of neuronal ceroid lipofuscinoses were 4.70 ± 3.48 years, 6.76 ± 4.49 years, and 7.27 ± 4.78 years, respectively. Findings on initial brain MR imaging included T2/FLAIR hypointensity in the thalami (n = 22); T2/FLAIR hyperintensity in the periventricular and deep white matter (n = 22), posterior limb of the internal capsule (n = 22), ventral pons (n = 19), and insular/subinsular region (n = 18); supratentorial (n = 21) and infratentorial atrophy (n = 20). Eight of 9 patients who had follow-up neuroimaging showed progressive changes.ConclusionsWe identified reported classic neuroimaging features in all except 1 patient with neuronal ceroid lipofuscinoses in our study. CLN2, CLN5, and CLN7 diseases showed predominant cerebellar-over-cerebral atrophy. We demonstrate that abnormal signal intensity in the deep white matter, posterior limb of the internal capsule, and ventral pons is more common than previously reported in the literature. We report abnormal signal intensity in the insular/subinsular region for the first time. The difference in the median time from disease onset and diagnosis was 1.5 years.

Dataset Information

Emerging new roles of the lysosome and neuronal ceroid lipofuscinoses.

Publications

Emerging new roles of the lysosome and neuronal ceroid lipofuscinoses.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets