Distortion of neuronal geometry and formation of aberrant synapses in neuronal storage disease

Purpura, Dominick P.; Suzuki, Kinuko

doi:10.1016/0006-8993(76)90245-6

Cited by 265 publications

(94 citation statements)

References 5 publications

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“…It is noteworthy that the experimental paradigm produced meganeurites only in CA1 neurons, because these cells constitute the hippocampal subpopulation most vulnerable to degeneration in Alzheimer's disease (AD) (West et al, 1994). Beyond this, it is possible that meganeurites are transitional structures generated by neurons as part of an exocytotic event (Purpura and Suzuki, 1976;Cavanagh et al, 1993). Data obtained from studies on the spinal ganglion suggest that cells remove structures similar to FDBs by pinching off recently generated cytoplasmic protrusions (Spoerri and Glees, 1973).…”

Section: Discussionmentioning

confidence: 99%

Suppression of Cathepsins B and L Causes a Proliferation of Lysosomes and the Formation of Meganeurites in Hippocampus

Bednarski¹,

Ribak

Lynch³

1997

J. Neurosci.

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Cultured hippocampal slices exhibited prominent ultrastructural features of brain aging after exposure to an inhibitor of cathepsins B and L. Six days of treatment with N-CBZ-Lphenylalanyl-L-alanine-diazomethylketone (ZPAD) resulted in a dramatic increase in the number of lysosomes in the perikarya of neurons and glial cells throughout the slices. Furthermore, lysosomes in CA1 and CA3 pyramidal cells were not restricted to the soma but instead were located throughout dendritic processes. Clusters of lysosomes were commonly found within bulging segments of proximal dendrites that were notable for an absence of microtubules and neurofilaments. Although pyknotic nuclei were sometimes encountered, most of the cells in slices exposed to ZPAD for 6 d appeared relatively normal. Slices given 7 d of recovery contained several unique features, compared with those processed immediately after incubation with the inhibitor. Cell bodies of CA1 neurons were largely cleared of the excess lysosomes but had gained fusiform, somatic extensions that were filled with fused lysosomes and related complex, dense bodies. These appendages, similar in form and content to structures previously referred to as "meganeurites," were not observed in CA3 neurons or granule cells. Because meganeurites were often interposed between cell body and axon, they have the potential to interfere with processes requiring axonal transport. It is suggested that inactivation of cathepsins B and L results in a proliferation of lysosomes and that meganeurite generation provides a means of storing residual catabolic organelles. The accumulated material could be eliminated by pinching off the meganeurite but, at least in some cases, this action would result in axotomy. Reduced cathepsin L activity, increased numbers of lysosomes, and the formation of meganeurites are all reported to occur during brain aging; thus, it is possible that the infusion of ZPAD into cultured slices sets in motion a greatly accelerated gerontological sequence.

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Section: Discussionmentioning

confidence: 99%

Suppression of Cathepsins B and L Causes a Proliferation of Lysosomes and the Formation of Meganeurites in Hippocampus

Bednarski¹,

Ribak

Lynch³

1997

J. Neurosci.

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“…Meganeurites were documented to occur specifically at the axon hillock area of pyramidal neurons and to push the sodium channel-rich initial segment of the axon more distal with their continued expansion (Walkley & Pierok 1986). In most storage diseases, meganeurite surfaces were found to be covered with synapses, or with postsynaptic densities lacking visible axonal contacts (Purpura & Suzuki 1976;Walkley et al 1981a). Neurons in some storage diseases, for example the NCLs, exhibited meganeurites that lacked spines, synapses and neuritic outgrowth.…”

Section: Ectopic Dendritogenesis Was Discovered In Gm2 Gangliosidosismentioning

confidence: 99%

Neurobiology and cellular pathogenesis of glycolipid storage diseases

Walkley

2003

Phil. Trans. R. Soc. Lond. B

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Disorders of lysosomal metabolism often involve the accumulation of specific types of glycolipid, particularly gangliosides, because of either degradative failure or other currently unknown mechanisms. Although the precise role of gangliosides in cells remains enigmatic, the presence of specific abnormalities secondary to ganglioside accumulation in lysosomal diseases has suggested important biological functions. Chief among these is the growth of new dendrites on particular classes of mature neurons secondary to an increase in GM2 ganglioside. That GM2 has also been shown to be elevated in normal immature neurons coincident with dendritic sprouting provides a compelling argument that this ganglioside plays a role in dendritic initiation. This discovery has led to the search for other regulators of dendritic differentiation that may in some way be linked to the expression and/or function of GM2 ganglioside. Principal candidates that have emerged include tyrosine kinase receptors, small GTPases and calcium/calmodulindependent protein kinase II. Understanding the mechanism underlying ectopic dendritogenesis in lysosomal diseases can be expected to generate significant insight into the control of dendritic plasticity in normal brain. The detrimental aspects of ganglioside accumulation in storage diseases as well as the potential link between gangliosides and dendritogenesis also provide a strong rationale for developing pharmacological means to manipulate ganglioside expression in neurons.

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“…It is known that an accumulation of inert macromolecular breakdown products with the neuron can, by altering its form, lead to neuropathological changes (Purpura and Suzuki, 1976). Such "geometric toxicity" has been described for several hereditary gangliosidoses.…”

Section: A Consolidated Theory Of Cerebral Oxidative Stress and Agingmentioning

confidence: 99%

Oxidative damage and cerebral aging

LeBel

Bondy

1992

Progress in Neurobiology

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Distortion of neuronal geometry and formation of aberrant synapses in neuronal storage disease

Cited by 265 publications

References 5 publications

Suppression of Cathepsins B and L Causes a Proliferation of Lysosomes and the Formation of Meganeurites in Hippocampus

Suppression of Cathepsins B and L Causes a Proliferation of Lysosomes and the Formation of Meganeurites in Hippocampus

Neurobiology and cellular pathogenesis of glycolipid storage diseases

Oxidative damage and cerebral aging

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