Clinical progression in Parkinson disease and the neurobiology of axons

Abstract

In spite of tremendous growth in recent years in our knowledge of the molecular basis of Parkinson's disease and the molecular pathways of cell injury and death, we remain without therapies that forestall disease progression. While there are many possible explanations for this lack of success, one is that experimental therapeutics to date have not adequately focused on an important component of the disease process, that of axon degeneration. It remains unknown what neuronal compartment, either the soma or the axon, is involved at disease onset, although some have proposed that it is the axons and their terminals that take the initial brunt of injury. Nevertheless, this concept has not been formally incorporated into many of the current theories of disease pathogenesis, and it has not achieved a wide consensus. More importantly, in view of growing evidence that the molecular mechanisms of axon degeneration are separate and distinct from the canonical pathways of programmed cell death that mediate soma destruction, the possibility of early involvement of axons in PD has not been adequately emphasized as a rationale to explore the neurobiology of axons for novel therapeutic targets. We propose that it is ongoing degeneration of axons, not cell bodies, that is the primary determinant of clinically apparent progression of disease, and that future experimental therapeutics intended to forestall disease progression will benefit from a new focus on the distinct mechanisms of axon degeneration.

A Progressive Mouse Model of Parkinson's Disease: The Thy1-aSyn (“Line 61”) Mice

“…Evidence from brain imaging studies suggests that axonal pathology precedes dopaminergic cell loss in PD [35]. However, even when examined at 22 months of age, Thy1-aSyn mice did not show any reduction in the number of TH-positive neurons, the classical marker for dopaminergic neurons, in the substantia nigra pars compacta, even though their diameter was slightly reduced.…”

“…As both environmental and genetic risk factors for PD become better known, it is likely that experimental manipulations will be found that cause dopamine cell loss in the Thy1-aSyn mice. In the meantime, neuroprotective strategies can be tested before and after the onset of striatal dopamine loss to determine whether they can prevent or slow down this critical aspect of PD pathology, which likely precedes cell body loss in patients as well [35].…”

Impaired neurotransmission caused by overexpression of α-synuclein in nigral dopamine neurons

“…1 for a recent review). Although genuine longitudinal data are difficult to obtain in human material, available postmortem data indicate that the loss of DA in the caudate nucleus at the time of onset of symptoms is on the order of 70-80%, whereas as much as 70% of the nigral DA cell bodies may still be alive (1)(2)(3)(4)(5). Measurement of binding to the vesicular monoamine transporter (VMAT), which is likely to be a good measure of the functional integrity of the DA terminals, has shown severe loss of VMAT in the caudate nucleus early in the disease in some patients (6).…”

A viral peptide that targets mitochondria protects against neuronal degeneration in models of Parkinson’s disease

“…T he progressive loss of structure and function of neurons in neurodegenerative diseases, including Parkinson's disease (PD), involves mitochondrial dysfunction and early axonal degeneration [1][2][3] . Accordingly, agents that could protect mitochondrial functions may have broad therapeutic implications, especially considering that we still lack efficient therapies to block neuronal demise in the early stages of neurodegeneration.…”