Mechanisms of neurodegeneration in neuronal ceroid-lipofuscinoses

Abstract

Neuronal ceroid-lipofuscinoses (NCL) are a group of neurodegenerative diseases and autosomal recessive lysosomal storage disorders. We examined the involvement of cell death, oxidative stress, and glutamate excitotoxicity using immunohistochemistry against Bcl-2, Bcl-x, oxidative products to proteins, lipids and DNA, calcium-binding proteins (calbindin-D28K, parvalbumin, calretinin), and glial glutamate transporters (excitatory amino acid transporters 1 and 2), in addition to terminal deoxynucleotidyl transferase-mediated dUTP-nick end labeling (TUNEL) in the brains from three cases of late infantile form of NCL (LINCL) and one case of juvenile form of NCL (JNCL) to investigate the neurodegenerative mechanisms. In the cerebral and cerebellar cortex, all of three LINCL cases demonstrated neurons with TUNEL-immunoreactive nuclei, whereas the JNCL case did not show TUNEL-immunoreactive nuclei. The coexistence of the nuclear TUNEL-immunoreactivity nuclei and cytoplasmic deposition of 4-hydroxy-2-nonenal-modified protein in the frontal cortex and hypoglossal nucleus may suggest a possible interrelationship between DNA fragmentation and lipid oxidation in LINCL. Additionally, glycoxidation of protein and oxidative stress to DNA seemed to be involved in the cerebellar and cerebral degeneration, respectively. Interneurons immunoreactive for calbindin-D28K and parvalbumin were severely reduced in the cerebral cortex, whereas those for calretinin were comparatively well preserved in LINCL, indicating the possibility of altered GABAergic system. The disturbance of expression of glial glutamate transporters seemed to be heterogeneous and mild. These findings suggest the possibility of new treatments for neurodegeneration in LINCL using antioxidative agents and/or GABAergic medications.

Oxidative stress in neurodegeneration in dentatorubral-pallidoluysian atrophy

“…It is possible that the aforementioned changes in this analysis may be secondary to epileptic seizures rather than causative. However, we immunohistochemically clarified the accumulation of oxidative products in the brains of neuronal ceroidlipofuscinosis (NCL), which can also cause PME [30,31]. Cases of late infantile and protracted juvenile types of NCL demonstrated accumulation of 8-OHdG and 4-HNE in the cerebral cortex.…”

Assessing Disease Severity in Late Infantile Neuronal Ceroid Lipofuscinosis Using Quantitative MR Diffusion-Weighted Imaging

“…A study found that calcium-binding proteins linked to GABAergic interneurons in the cortex and cerebellum were disrupted in patients with LINCL. 24 An additional postmortem study of 13 case subjects with LINCL found a moderate-to-severe loss of myelin and mild-to-moderate gliosis in the periventricular white matter of 10 of 13 case subjects. 2 Increased signal intensity in the periventricular white matter on T2-weighted MR images in patients with LINCL was correlated with histology confirming atrophy.…”

Common and Uncommon Pathogenic Cascades in Lysosomal Storage Diseases

“…In MPSIIIB, enhanced oxidative stress resulted in protein, lipid, and DNA oxidation (24), and an oxidative imbalance was found in MPSI (25). In NCLs, elevated ROS and superoxide dismutase levels were suggested to be downstream to ER stress (26), a significant increase in manganese-dependent superoxide dismutase activity was detected in fibroblasts and brain extracts from CLN6 sheep (27), and increased expression of 4-hydroxynonenal was detected in late infant and juvenile forms of NCL (28).…”