Storage solutions: treating lysosomal disorders of the brain

Abstract

Many neurodegenerative diseases are characterized by the accumulation of undegradable molecules in cells or at extracellular sites in the brain. One such family of diseases is the lysosomal storage disorders, which result from defects in various aspects of lysosomal function. Until recently, there was little prospect of treating storage diseases involving the CNS. However, recent progress has been made in understanding these conditions and in translating the findings into experimental therapies. We review the developments in this field and discuss the similarities in pathological features between these diseases and some more common neurodegenerative disorders.

Development of a Rab9 Transgenic Mouse and Its Ability to Increase the Lifespan of a Murine Model of Niemann-Pick Type C Disease

“…24 In agreement with previous reports, the NPC mut/mut sample showed a large accumulation of microglia with the typical amoeboid morphology characteristic of activated cells, whereas only ramified (resting) microglia were seen in NPC WT/WT animals. 4,22,25 However, there was no obvious difference in NPC mut/mut mice with or without expression of the Rab9 transgene in either 7-or 10-week-old animals (data not shown). ii) Weight loss.…”

Gangliosides as apoptotic signals in ER stress response

“…Pathophysiologic studies of patients and animal models have identified changes in neuronal connectivity in the cerebral cortex, including degeneration of axons and synapses of inhibitory neurons (axon swelling or 'spheroids'), regrowth of dendrites (ectopic dendrites or meganeurites), and formation of new synapses of pyramidal neurons. [17][18][19][20] Many of these phenomena have been attributed to ganglioside storage, albeit the underlying molecular effectors are still unknown. Neuronal cell death and demyelination occur in some of these LSDs [21][22][23] and are often accompanied by astrogliosis and microgliosis that appear mostly in areas of severe neuronal vacuolation.…”

Nanomedicine in the diagnosis and therapy of neurodegenerative disorders

“…Current treatment modalities for LSDs are bone marrow transplantation together with enzyme replacements. These provide benefit to visceral manifestations but not address the CNS pathologies that are both a common and significant signature for disease [58]. These are limited as therapeutic agents cannot cross the BBB.…”