Paraneoplastic cerebellar degeneration: Yo antibody alters mitochondrial calcium buffering capacity.

AIM:

Neurodegeneration is associated with dysfunction of calcium buffering capacity and thereby sustained cellular and mitochondrial calcium overload. Paraneoplastic cerebellar degeneration (PCD), characterized by progressive Purkinje neuron degeneration following paraneoplastic Yo antibody internalisation and binding to cerebellar degeneration-related protein CDR2 and CDR2L, has been linked to intracellular calcium homeostasis imbalance due to calbindin D_28kmalfunction. Therefore, we hypothesized that Yo antibody internalisation affects not only calbindin calcium binding capacity but also calcium-sensitive mitochondrial-associated signalling, causing mitochondrial calcium overload and thereby Purkinje neuron death.

METHODS:

Immunohistochemically, we evaluated cerebellar organotypic slice cultures of rat brains after inducing PCD through the application of Yo antibody positive PCD patient sera or purified antibodies against CDR2 and CDR2L how pharmacologically biased mitochondrial signalling affected PCD pathology.

RESULTS:

We found that Yo antibody internalisation into Purkinje neurons caused depletion of Purkinje neuron calbindin-immunoreactivity, cannabinoid 1 receptor over-activation and alterations in the actions of the mitochondria permeability transition pore (MPTP), voltage-dependent anion channels, reactive oxygen species (ROS), and Na⁺ /Ca²⁺ exchangers (NCX). The pathological mechanisms caused by Yo antibody binding to CDR2 or CDR2L differed between the two targets. Yo-CDR2 binding did not alter the mitochondrial calcium retention capacity, cyclophilin D-independent opening of MPTP or activity of NCX.

CONCLUSION:

These findings suggest that minimising intracellular calcium overload toxicity either directly with cyclosporin-A or indirectly with cannabidiol or the ROS scavenger butylated hydroxytoluene promotes mitochondrial calcium homeostasis and may therefore be used as future neuroprotective therapy for PCD patients. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.