SUMMARY Recent genome-wide association studies have linked common variants in the human genome to Parkinson’s disease (PD) risk. Here we show that the consequences of variants at 2 such loci, PARK16 and LRRK2, are highly interrelated, both in terms of their broad impacts on human brain transcriptomes of unaffected carriers, and in terms of their associations with PD risk. Deficiency of the PARK16 locus gene RAB7L1 in primary rodent neurons, or of a RAB7L1 orthologue in Drosophila dopamine neurons, recapitulated degeneration observed with expression of a familial PD mutant form of LRRK2, whereas RAB7L1 overexpression rescued the LRRK2 mutant phenotypes. PD-associated defects in RAB7L1 or LRRK2 led to endolysosomal and Golgi apparatus sorting defects and deficiency of the VPS35 component of the retromer complex. Expression of wild-type VPS35, but not a familial PD-associated mutant form, rescued these defects. Taken together, these studies implicate retromer and lysosomal pathway alterations in PD risk.

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α-Synuclein (aSyn) is implicated both in physiological functions at neuronal synaptic terminals as well as pathological processes in the context of Parkinson’s disease (PD). However, the molecular mechanisms for these apparently diverse roles are unclear. Here we show that specific RNA transcript isoforms of aSyn with an extended 3′UTR, aSynL, appear selectively linked to pathological processes, relative to shorter aSyn transcripts. Common variants in the aSynL 3′UTR associated with PD risk promote the accumulation and translation of aSynL transcripts. The presence of intracellular dopamine can further enhance the relative abundance of aSynL transcripts through alternative polyadenylation (PolyA) site selection. We demonstrate that presence of the extended aSynL transcript 3′UTR impacts accumulation of aSyn protein, which appears redirected away from synaptic terminals and towards mitochondria, reminiscent of PD pathology. Taken together, these findings identify a novel mechanism for aSyn regulation in the context of PD-associated genetic and environmental variation.

Dopamine plays a central role in motivating and modifying behavior, serving to invigorate current behavioral performance and guide future actions through learning. Here we examine how this single neuromodulator can contribute to such diverse forms of behavioral modulation. By recording from the dopaminergic reinforcement pathways of the Drosophila mushroom body during active odor navigation, we reveal how their ongoing motor-associated activity relates to goal-directed behavior. We find that dopaminergic neurons correlate with different behavioral variables depending on the specific navigational strategy of an animal, such that the activity of these neurons preferentially reflects the actions most relevant to odor pursuit. Furthermore, we show that these motor correlates are translated to ongoing dopamine release and acutely perturbing dopaminergic signaling alters the strength of odor tracking. Context-dependent representations of movement and reinforcement cues are thus multiplexed within the mushroom body dopaminergic pathways, enabling them to coordinately influence both ongoing and future behavior.

In the original publication of this manuscript (p. 277), the value of the parameter dz b describing the voltage dependence of Hv1 block by 2GBI was incorrectly reported to be 0.35 ± 0.1, while it is actually 0.25 ± 0.01. This means that 2GBI can experience up to 25% of the total electric field when moving in and out of its binding site. The error does not affect the discussion of the findings or the conclusions of the paper.