Parkinson’s disease is the second most common neurodegenerative disorder after Alzheimer’s disease and is estimated to affect approximately 1–4% of individuals aged over 60 years old. Although considerable efforts have been invested into developing disease‐modifying therapies for Parkinson’s disease, such efforts have been confounded by the difficulty in accurately diagnosing Parkinson’s disease during life to enable accurate patient stratification for clinical trialling of candidate therapeutics. Therefore, the search for effective biomarkers that can be accurately evaluated during life with non‐invasive means is a pressing issue in the field. Since the discovery of α‐synuclein (α‐syn) as a protein linked to a familial form of Parkinson’s disease, later identified as the major protein component of the neuropathological hallmark of idiopathic Parkinson’s disease, considerable interest has focused on this protein and its distinct conformers. We describe here the progress that has been made in the area of Parkinson’s disease biomarker discovery with a focus on α‐synuclein. In particular, we highlight the novel assays that have been employed and the increasing complexity in evaluating α‐synuclein with regard to the considerable diversity of conformers that exist in the biofluids and peripheral tissues under disease conditions. “This article is part of the Special Issue Synuclein.”

The control of movements is a fundamental feature shared by all animals. At the most basic level, simple movements are generated by coordinated neural activity and muscle contraction patterns that are controlled by the central nervous system. How behavioral responses to various sensory inputs are processed and integrated by the downstream neural network to produce flexible and adaptive behaviors remains an intense area of investigation in many laboratories. Due to recent advances in experimental techniques, many fundamental neural pathways underlying animal movements have now been elucidated. For example, while the role of motor neurons in locomotion has been studied in great detail, the roles of interneurons in animal movements in both basic and noxious environments have only recently been realized. However, the genetic and transmitter identities of many of these interneurons remains unclear. In this review, we provide an overview of the underlying circuitry and neural pathways required by Drosophila larvae to produce successful movements. By improving our understanding of locomotor circuitry in model systems such as Drosophila, we will have a better understanding of how neural circuits in organisms with different bodies and brains lead to distinct locomotion types at the organism level. The understanding of genetic and physiological components of these movements types also provides directions to understand movements in higher organisms.

Synucleinopathies including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA) are characterized by pathological accumulation of α-synuclein (α-syn). Amongst the various approaches attempting to tackle the pathological features of synucleinopathies, antibodybased immunotherapy holds much promise. However, the large size of antibodies and corresponding difficulty in crossing the blood-brain barrier has limited development in this area. To overcome this issue, we engineered single-chain variable fragments (scFvs) against fibrillar α-syn, a putative diseaserelevant form of α-syn. The purified scFvs showed specific activity towards α-syn fibrils and oligomers in comparison to monomers and recognized intracellular inclusions in human post-mortem brain tissue of Lewy body disease cases, but not aged controls. In vitro studies indicated scFvs inhibit the seeding of α-syn aggregation in a time-dependent manner, decreased α-syn seed-induced toxicity in a cell model of PD, and reduced the production of insoluble α-syn phosphorylated at Ser-129 (pS129-α-syn). These results suggest that our α-syn fibril-specific scFvs recognize α-syn pathology and can inhibit the aggregation of α-syn in vitro and prevent seeding-dependent toxicity. Therefore, the scFvs described here have considerable potential to be utilized towards immunotherapy in synucleinopathies and may also have applications in ante-mortem imaging modalities. Synucleinopathies are a group of neurodegenerative disorders comprising Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA) 1. PD is clinically characterized by motor symptoms of bradykinesia, unsteady gait and resting tremor that precedes cognitive impairment whilst, in contrast, DLB manifests as a cognitive disorder that often leads to motor features 2. However, despite differences in the sequence of clinical symptomatology, PD and DLB are both neuropathologically characterized by accumulations of the protein α-synuclein (α-syn) in vulnerable neurons as Lewy bodies (LBs) and in neuronal processes as Lewy neurites 3. MSA is characterized by α-syn aggregates in oligodendroglia as Papp-Lantos bodies/glial cytoplasmic inclusions 4 , though neuronal accumulations of α-syn are also observed 5. Several lines of evidence indicate that α-syn aggregation is a critical pathogenic event in the natural history of Lewy body diseases. α-Syn is the major protein component of LBs, various point mutations and/or multiplications in the α-syn gene have been described in familial PD, exogenous expression of α-syn in Drosophila and transgenic mice induce the formation of PD-like pathological phenotypes and behavior, and down-regulation of the α-syn protein reduces risk of developing PD 6-13. Although α-syn is implicated in PD risk, it is also thought to have important neuronal functions as it is a relatively abundant protein, comprising 0.5-1% of the total protein in soluble cytosolic brain fractions 14,15. Although α-syn is a soluble, monomeric, unfo...