Are we listening to everything the PARK genes are telling us?

Abstract

The cardinal motor symptoms that define Parkinson's disease (PD) clinically have been recognized for over 200 years. That these symptoms arise following the loss of dopamine neurons in the substantia nigra has been known for the last 50. These long-established facts have fueled a broadly held expectation that degenerating dopaminergic neurons alone hold the key to understanding and curing PD. This prevalent expectation is at odds with the observation that many nonmotor symptoms, including depression and cognitive inflexibility among others, can appear years earlier than the overt dopaminergic neuron degeneration that drives motor abnormalities and are not improved by levodopa treatment. Thus, preserving or rescuing dopamine neuron health and function is of paramount importance, but this alone fails to capture the underlying neurobiology of earlier-appearing nonmotor symptoms. Insight into the complete landscape of disease-related abnormalities and the context in which they arise can be gleaned from a more comprehensive consideration of the PARK genes that are known to cause PD. Here, we make the case that a full incorporation of research showing when and where PARK genes are expressed as well as the impact of gene mutation on function throughout life, in tandem with research studying how dopaminergic neuron degeneration begins, is essential for a full understanding of the multi-dimensional etiology of PD. A broad view may also reveal something about long-term adjustments cells and systems make in response to gene mutation and help to identify mechanisms conferring the resilience or susceptibility of some cells and systems over others. K E Y W O R D Scritical periods, development, nonmotor symptoms, PARK genes, Parkinson's disease, protein degradation, protein trafficking

Origins of Parkinson’s Disease in Brain Development: Insights From Early and Persistent Effects of LRRK2-G2019S on Striatal Circuits

“…The clinical management of PD largely focuses on the lateonset motor symptoms, leading in some cases to an almost tacit view that the cellular and synaptic environment in brains of PD patients is normal until the prodromal stage, at which time some pathophysiological process arises to co-opt and disrupt brain circuits and set a course of steady, degenerative decline. Based in part on genetic forms of late-onset PD and the mouse models used to mechanistically interrogate the impact of such mutations on cell and circuit function, there is growing recognition that this view probably does not adequately capture the complexity of the disease process or the cellular/circuit environment in the brain in which the disease manifests (Hemmerle et al, 2012;Irwin et al, 2013;Kannarkat et al, 2013;Benson and Huntley, 2019). In this focused review, we highlight mouse studies of LRRK2 and the prevalent G2019S mutation to underscore the broader, central thesis that PD-related gene mutations -present during brain development and beyond -exert significant effects on establishment and maturation of relevant circuits that impact their function, and perhaps viability, throughout life.…”

LRRK2 at Striatal Synapses: Cell-Type Specificity and Mechanistic Insights

“…Anatomically, LRRK2 mRNA is expressed at low levels across most of the brain, but it is specifically enriched in brain regions receiving dopaminergic input, including the cerebral cortex and striatum [ 43 , 49 , 50 ]. Semiquantitative in situ hybridization and quantification of transcripts by qPCR indicates that expression in mouse, rat, and human tissue is highest in the striatum, including the nucleus accumbens, and the cerebral cortex.…”

“…In addition to the phenotypes observed at dopaminergic neurons, LRRK2 knock-in models reveal altered structure, function, and plasticity at striatal synapses [ 59 , 74 , 76 , 78 , 79 , 80 ]. This has led to increasing recognition that LRRK2 is functionally relevant in the basal ganglia prior to old age and in a context that may be distinct from neurodegeneration; in addition, it may contribute to neurodegeneration later in life [ 41 , 49 ]. As previously discussed, LRRK2 expression in the cortex and striatum increases gradually, starting in the first postnatal week through 21 days of age [ 41 , 42 , 43 , 46 , 47 ].…”

Midbrain Organoids: A New Tool to Investigate Parkinson’s Disease

“…However, this is a limitation that certainly will be investigated in the future. By deriving further hMOs that carry defects in genes that are known to cause PD we could broaden the understanding of disease-related abnormalities and the context in which they arise (Benson and Huntley, 2019). The patient-specific nature of these models also opens promising avenues for future personalized medicine approaches (Bu et al, 2016;Hillje and Schwamborn, 2016;Smits et al, 2019b).…”