Reduced axonal transport in Parkinson's disease cybrid neurites is restored by light therapy

Patricia A Trimmer,Kathleen M Schwartz,Luis De Taboada,M Kathleen Borland,Uri Oron,Jackson Streeter

doi:10.1186/1750-1326-4-26

Abstract

BackgroundIt has been hypothesized that reduced axonal transport contributes to the degeneration of neuronal processes in Parkinson's disease (PD). Mitochondria supply the adenosine triphosphate (ATP) needed to support axonal transport and contribute to many other cellular functions essential for the survival of neuronal cells. Furthermore, mitochondria in PD tissues are metabolically and functionally compromised. To address this hypothesis, we measured the velocity of mitochondrial movement in human transmitochondrial cybrid "cytoplasmic hybrid" neuronal cells bearing mitochondrial DNA from patients with sporadic PD and disease-free age-matched volunteer controls (CNT). The absorption of low level, near-infrared laser light by components of the mitochondrial electron transport chain (mtETC) enhances mitochondrial metabolism, stimulates oxidative phosphorylation and improves redox capacity. PD and CNT cybrid neuronal cells were exposed to near-infrared laser light to determine if the velocity of mitochondrial movement can be restored by low level light therapy (LLLT). Axonal transport of labeled mitochondria was documented by time lapse microscopy in dopaminergic PD and CNT cybrid neuronal cells before and after illumination with an 810 nm diode laser (50 mW/cm2) for 40 seconds. Oxygen utilization and assembly of mtETC complexes were also determined.ResultsThe velocity of mitochondrial movement in PD cybrid neuronal cells (0.175 +/- 0.005 SEM) was significantly reduced (p < 0.02) compared to mitochondrial movement in disease free CNT cybrid neuronal cells (0.232 +/- 0.017 SEM). For two hours after LLLT, the average velocity of mitochondrial movement in PD cybrid neurites was significantly (p < 0.003) increased (to 0.224 +/- 0.02 SEM) and restored to levels comparable to CNT. Mitochondrial movement in CNT cybrid neurites was unaltered by LLLT (0.232 +/- 0.017 SEM). Assembly of complexes in the mtETC was reduced and oxygen utilization was altered in PD cybrid neuronal cells. PD cybrid neuronal cell lines with the most dysfunctional mtETC assembly and oxygen utilization profiles were least responsive to LLLT.ConclusionThe results from this study support our proposal that axonal transport is reduced in sporadic PD and that a single, brief treatment with near-infrared light can restore axonal transport to control levels. These results are the first demonstration that LLLT can increase axonal transport in model human dopaminergic neuronal cells and they suggest that LLLT could be developed as a novel treatment to improve neuronal function in patients with PD.

Highlights

It has been hypothesized that reduced axonal transport contributes to the degeneration of neuronal processes in Parkinson's disease (PD)
In this study we showed that the velocity of mitochondrial movement by axonal transport was significantly reduced in a human neuronal model of sporadic PD
Speculation that reduced axonal transport plays a role in PD pathogenesis has existed for some time

Summary

Introduction

It has been hypothesized that reduced axonal transport contributes to the degeneration of neuronal processes in Parkinson's disease (PD). Mitochondria in PD tissues are metabolically and functionally compromised To address this hypothesis, we measured the velocity of mitochondrial movement in human transmitochondrial cybrid "cytoplasmic hybrid" neuronal cells bearing mitochondrial DNA from patients with sporadic PD and disease-free age-matched volunteer controls (CNT). Reduced or compromised axonal transport could underlie the progressive, relentless loss of dopaminergic nerve terminals in sporadic PD. [9] Neurotoxins that are used to model PD pathogenesis (1-methyl-4-phenylpyridinium (MPP+) and rotenone) compromise mitochondrial function by inhibiting complex I of the mtETC. These toxins have microtubule depolymerizing activities that alter axonal transport. These toxins have microtubule depolymerizing activities that alter axonal transport. [2,10,11,12,13,14] Complex I of the mtETC is structurally and functionally defective in brain, platelets and other tissues in PD patients. [15,16] Since mitochondrial DNA (mtDNA) encodes components of the mtETC, it is not surprising that mtDNA from PD patients contains increased levels of mutations and deletions. [15,17,18,19]

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