Selectivity and Types of Cell Death in the Neuronal Ceroid Lipofuscinoses (NCLs)

Abstract

Cloning of the individual genes that are mutated in the neuronal ceroid lipofuscinoses (NCLs), or Batten disease, has opened up new avenues of research into the pathogenesis of these fatal autosomal recessive storage disorders. Genetically accurate mouse models have now been generated for each major form of the disorder, together with several variant forms. Ongoing analysis of these mice is revealing significant new data about the staging and progression of disease phenotypes. Combined with data from human autopsy tissues and large animal models, it is now clear that neurodegeneration is initially selective in the NCL CNS, targeting specific regions and particular cell populations. There is also evidence of selective glial activation that appears to precede obvious neurodegeneration, becoming more widespread with disease progression. Currently, there is debate over the mechanisms of cell death that operate in each form of NCL, with evidence of both apoptosis and autophagy. It is likely that these mechanisms may encompass a spectrum of cell death events, depending upon the specific context of each neuronal population. Taken together, these data have significant clinical implications for the development and targeting of appropriate therapeutic strategies, and for providing the landmarks to judge their efficacy.

Murine Cathepsin F Deficiency Causes Neuronal Lipofuscinosis and Late-Onset Neurological Disease

“…EM investigation of the spinal cord confirmed the presence of membrane-bound lipofuscin granules with fingerprint profiles, a finding indicative of lysosomal lipofuscin accumulation. These findings are similar to observations in mice and humans with more gross defects in endosomal/lysosomal function (15,21,23,40). However, cat F is the only endoprotease whose inactivation alone causes widespread but exclusively CNS lipofuscin accumulation.…”

“…Immunohistochemical staining for the glial cell marker GFAP in brain and spinal cord sections revealed substantial gliosis in cat F Ϫ/Ϫ mice compared to agematched WT controls (Fig. 4B), which indicates neuronal stress or neurodegeneration (9) and which occurs in NCL patients and mouse models (21,38). Quantification of GFAP staining in four matched regions of the cortex and spinal cord demonstrated an average of ϳ6.7-fold increase in gliosis in cat (Fig.…”

High Resolution 1H NMR-based Metabolomics Indicates a Neurotransmitter Cycling Deficit in Cerebral Tissue from a Mouse Model of Batten Disease

“…The disorders are typified by their progressive nature with symptoms including visual disturbances, psychomotor deterioration, mental impairment, worsening seizures, blindness, and, ultimately, premature death (3)(4)(5)(6)(7). Furthermore, all share the histopathological finding of accumulation of autofluorescent lipopigment in lysosomes, similar to the pigment lipofuscin found in normal aging brains (8, 9), and ceroid, found in pathological conditions (10).…”

Genetic Modifiers of Drosophila Palmitoyl–Protein Thioesterase 1-Induced Degeneration

“…This loss of protein function may have a primary effect on specific cellular processes or signal transduction mechanisms, leading directly or through secondary effects to the observed disease pathology (reviewed in Futerman and van Meer 2004). Work on NCLs, including INCL, in mice, sheep, and humans has described the amount and regional location of cellular storage material in affected brains and compared it to the progressive cellular pathology seen in each subtype (Bible et al 2004;Mitchison et al 2004). These analyses suggest no clear connection between the amount of storage material and the observed neurodegeneration in these systems, leading to the hypothesis that it is the disruption of certain cellular processes or signaling pathways in the patient's neuronal cells that produces dysfunction and degeneration (Oswald et al 2005).…”