Open research questions in Parkinson's Disease Mechanisms and Treatments

What the literature leaves open

• Future work should focus on multimodal data integration, external dataset evaluation, and implementation on real quantum hardware to assess practical feasibility. These factors Future research should focus on validating the proposed framework using larger and more diverse multi-center datasets to improve generalizability across different populations.

  Quantum-classical hybrid learning framework for Parkinson’s disease prediction using acoustic and clinical features · 2026 · DOI

• Microbiota-based treatments for prodromal PD, which is accompanied by a wide range of neuropsychiatric symptoms, are being considered a potential early intervention but are still under-investigated.

  Coexistence of anhedonia and sensation-seeking with context-dependent gut dysbiosis in a prodromal transgenic mouse model of Parkinson’s disease · 2026 · DOI

• The biochemical mechanisms driving iron dyshomeostasis in PD brain and whether these are early or late events in the neurodegenerative process remain unknown.

  Parkinson’s disease LRRK2 mutations dysregulate iron homeostasis and promote oxidative stress and ferroptosis in human neurons and astrocytes · 2026 · DOI

• Large-scale prospective clinical studies with protein-level biomarker assessment, tau-PET imaging, and independent multi-cohort transcrip- tomic validation are warranted before CSF total tau can be considered a candidate biomarker for PD progression.

  The Association Between Alzheimer’s Disease-Related Biomarkers And Parkinson’s Disease Based On Single-Cell Sequencing Analysis Combined With Mendelian Randomization · 2026 · DOI

• Introduction Neuropsychiatric manifestations, such as impulse control disorders (ICD) and apathy, are common in Parkinson's disease (PD) and significantly impact patient quality of life, yet their underlying neuroanatomical substrates remain poorly understood.

  Explainable 3D vision transformer framework for detecting brain anomalies in neuropsychiatric subtypes of Parkinson's disease · 2026 · DOI

• However, the interplay between LRRK2 GTPase and kinase domains, and with the surrounding scaffold regions has remained underexplored, with implications for the prediction of on- and off-target effects associated with kinase inhibition.

  Loss of catalytic activity and impaired proteostasis in guanosine nucleotide-depleted LRRK2 · 2026 · DOI

• Despite these advances, several critical barriers continue to limit clinical translation, including biological heterogeneity, methodolog- ical variability, the lack of standardized analytical work- flows, limited reproducibility across independent studies, and inadequate validation in large, multicentre, longitudinal cohorts.

  Multi-omics approaches to parkinsonism: genomic, proteomic, and non-coding RNA perspectives · 2026 · DOI

• BackgroundParkinsons disease (PD) has a prolonged prodromal phase, but minimally invasive molecular biomarkers distinguishing manifest PD from prodromal synucleinopathy remain insufficiently characterized.

  Blood transcriptomics reveals a Parkinson's disease signature and heterogeneous prodromal molecular profiles in isolated RBD · 2026 · DOI

• Sex and genetic factors influence the epidemiology and clinical features of Parkinsons disease (PD), but their impact on N-methyl-D-aspartate receptor (NMDAR)-related amino acids remains unclear.

  Sex and genotype influence the disruption of circulating NMDAR-related amino acids in patients with Parkinson's disease · 2026 · DOI

• However, the temporal relationship between midbrain dopaminergic (DA) neurodegeneration, M1 circuit dysfunction, and Parkinsonian motor symptoms remains poorly understood.

  Emergence of Task-Related Motor Cortical Dysfunction in Mice with Progressive Parkinsonism · 2026 · DOI

• Lewy body diseases, including Parkinsons disease (PD) and dementia with Lewy bodies (DLB), are defined by neuronal accumulation of misfolded -synuclein (-Syn), yet the ultrastructural diversity of these inclusions across brain regions and disease contexts remains unclear.

  Correlative Ultrastructural Mapping of Lewy Pathology Reveals Regional Diversity in Parkinsons and Dementia with Lewy bodies · 2026 · DOI

• Interestingly, these effects were limited to the striatum, with no increases seen in the striatum, ventral tegmental area, or frontal cortex ConclusionLevodopa triggers processes that increase iron deposition in the substantia nigra, but this process may not depend on dopamine neurons.

  Levodopa increases substantia nigra iron: implications for Parkinson's disease · 2026 · DOI

• Indeed, co-expression of LRRK2 with RAB29 induces a hyperactivation of LRRK2 kinase activity, however the role of the LRRK2 heterologous phosphorylation status in its activation remains unknown.

  The phosphorylation status of LRRK2 at the S910/S935 cluster determines its sensitivity to activation by RAB29 · 2026 · DOI

• This review delineates the underlying mechanisms of the pathological triad of PD: abnormal α-Syn proteotoxicity, mitochondrial dysfunction, and neuroinflammation within the disease milieu. Furthermore, it elucidates how these components establish a self-perpetuating vicious cycle through intricate reciprocal crosstalk and bidirectional feedback loops. Building upon the aforementioned mechanisms, this review synthesizes the therapeutic landscape directed at the pathological triad of PD. Furthermore, we delineate synergistic intervention frameworks specifically designed to disrupt the pathological interaction axes that drive disease progression. Notwithstanding substantial strides in deciphering PD pathogenesis and exploring therapeutic interventions, several critical hurdles persist, categorized into three major dimensions. (1) Elucidating the role of mitoxyperiosis, a 5 2 0 2,. l a t e i e W, s l e v e l H S G d n a D O S g n i t a v e l e y l l a c i t s i g r e n y S l e d o m l l e c 2 1 C P d e c u d n i - + P P M n i r a l l e t u c s, e n o v a r a d e f o s m s i n a h c e m t n e r e ff i d h t i w s g u r d f o n o i t a n i b m o C, s e n i k o t y c y r o t a m m a fl n i f o e s a e l e r e h t g n i c u d e r y t i c a p a c c i t o t p o p a - i t n a r a l u l l e c g n i c n a h n e d n a n o i t c a - m u n e h t g n i s a e r c n i d n a, I x e l p m o c l a i r d n o h c o t i m s l l e c e v i t i s o p - H T f o r e b 4 2 0 2,. l a t e k i r v a K d n a, 2 - l c B, F N D B f o n o i s s e r p x e e h t g n i t a l u g e r p U l e d o m e s u o m D P d e c u d n i - P T P M n i m r o f t e m, e n o n i u q o m y h T 4 2 0 2,. l a t e m K i, n o i t c n u f s y d r o t o m - n o n g n i v o r p m i y l l a c i t s i g r e n y S l e d o m e s u o m D P d e c u d n i - P T P M A P O D - L, l o a g o h s - 6 7 1 0 2,. l a t e o a h Z s y a w h t a p g n i l a n g i s l a r u e n g n i t a l u d o m y l l a c i t s i g r e n y S l e d o m e s u o m D P d e c u d n i - P T P M A P O D - L, s e d i s o n e p y G l a n o i t i d a r T m o r f s t n e i d e r g n i e v i t c a f o n o i t a n i b m o C d n a 2 / 1 K R E f o n o i t a l y r o h p s o h p e h t g n i t i b i h n i d n a s u p m a c o p p i h e h t n i B E R C s g u r d l a n o i t n e v n o c d n a) M C T ( e n i c i d e M e s e n i h C s e c n e r e f e R s m s i n a h c e m l a t n e m a d n u F l e d o m t n e d o R l e d o m o r t i v n i / s e i t i l a d o m n o i t n e v r e t n I n o i t n e v r e t n i r o f s n o i t c e r i D s e x a n o i t c a r e t n i l a c i g o l o h t a p n o d e s a b s e i g e t a r t s y p a r e h t d e t e g r a t c i t s i g r e n y S 4 e l b a T 8 1 0 2,.

  The vicious cycle: unraveling the interplay between α-synuclein, mitochondrial dysfunction, and neuroinflammation in Parkinson’s disease · 2026 · DOI

• While the precise mechanisms for PD-related cognitive decline and sleep disturbances are not fully understood, research suggests several potential contribu- tors: (1) Alterations in brain structure, including atrophy in the fron- tal, parietal, and temporal lobes and the hippocampus, as well as compromised white matter integrity in key tracts (e.

  Traditional Chinese exercise for quality of life, cognition, sleep in Parkinson’s disease: a systematic review and meta-analysis · 2026 · DOI

• Future research should focus on elucidating the precise mechanisms of early pain in PD and developing targeted, effective interventions. Also, the lack of data on co-existent confounding conditions like diabetic neuropathy, osteoarthritis, and Journal of Health and Allied Sciences NU • Article in Press • 8 spondyloarthropathies may influence the clinical pain profile.

  The Clinical Profile of Pain as a Non-motor Symptom in Parkinson’s Disease: A South Indian Experience · 2026 · DOI

• Care recommendations Prospective cohort; mixed methods PubMed & CINAHL Donizak, McCabe, Pharmacological management of patients with Parkinson’s disease in the acute hospital setting: a review Queen, Caring for patients with Parkinson’s disease in general hospital settings Ellis et al., Supporting Parkinson’s disease medication safety for nurses in the acute care setting through an educational intervention study Boudreaux et al., Improving Medication Management for Inpatients…

  Core themes of high quality, safe inpatient care for people with PD · 2026 · DOI

• However, the prior study was limited to a hospital-based cohort and did not include a general population control group, nor did it quantify the relative risk of anxiety disorders in the form of hazard ratios or other comparative risk estimates. However, this study was likewise limited to a small, hospital- based cohort, had a relatively short follow-up period, and focused on descriptive analyses of the presence and temporal changes of anxiety symptoms, without quantitatively assessing the risk of incident anxiety disorders in comparison with a general population control group.

  Incidence of anxiety disorders following Parkinson’s disease: a population-based cohort study · 2026 · DOI

• is increasingly being challenged. Clinical trials targeting this pathophysiological hallmark, specifically the intracellular accumulation of alpha-synuclein, have consistently yielded negative results despite rigorous methodology.29 Given this outcome, the diverse and intricate variations observed among PD patients, the successful strides of systems biology in fields like oncology, 8 Data-Driven Subtyping & Stratification Program particularly in cancer research, and the holistic perspective proffered by systems biology, there's a growing call among researchers to pivot towards understanding the unique biological intricacies that underpin the pathology of PD. Delving into these detailed differences may pave the way for more tailored and efficacious therapeutic strategies.35 Figure 3 illustrates the proposed shift in perspective regarding PD manifestations. Figure 2 - Illustration of the traditional clinico-pathological perspective on PD and its evolution in the context of systems biology A) Reductionism: the Duck of Vaucanson. This engraving of the Canard Digérateur or “Digesting Duck” illustrated the famous mechanical duck made by Jacques de Vaucanson in the 18th century, which supposedly ate grain and excreted droppings in front of an audience unaware such stool pellets were not manufactured by the contraption but placed surreptitiously. The “Duck of Vaucanson” served to illustrate Descartes view (in De Homine, 1662) that all animals could be reductively explained as automata. We have reductively attempted to explain the large range of clinical, pathologic, genetic, and molecular findings into a single “Duck of Parkinson,” represented by each of the wheels, levers, and pipes of a single contraption (Copyright in public domain via Wikimedia Commons). B) Systems biology: Looks like a duck, walks like a duck, but there are differences. Modifications of the Duck of Vaucanson illustrate the systems biology model of Parkinson diseases. It acknowledges distinctive self-regulating “mechanical” systems within each of these “birds” (distinct pathophysiological processes), yet sharing enough external and internal duck-like features to belong to the same “family” but with a phenotype shaped by the “pond where they swim” (colored circles surrounding the ducks). Each “pond” includes a combination of genetic, molecular, and environmental traits that combine in systems biology networks (shades of yellow, blue, green, and red). These “Parkinson ducks” represent an oversimplification of more complicated interactions (e.g., mosaicism might have an effect on all genetic factors, mono- and polygenic; similarly, microbiota on metagenomics, etc.).

  Project Methods for A Machine-learning Approach To Derive Biology-driven Parkinson's Disease Subtypes And Predict Longitudinal Clinical Outcomes Across Multiple Cohorts · 2026 · DOI

• In considering future directions for the use of trazodone for depression in PD patients, the experts acknowledge that it would be useful to carry out an observational, multicenter study to understand routine clinical practice, assessing treatment effectiveness using validated scales for anxiety and depression. Standardized criteria are used to diagnose depression in PD, but unfortunately scales for monitoring anxiety and depression are not commonly used in daily clin- ical practice. Moreover, a standardized approach to evaluate the effectiveness of treatments on affective components is lacking. The experts also agreed that neurologists need greater education regarding both the pathophysiology and the clini- cal manifestations of depression and the pharmacokinetic characteristics of trazodone, and especially its dose-depen- dent effects. For this purpose, training materials and focused events may be useful to raise awareness about this impor- tant topic, particularly in young neurologists. To achieve the full benefits of trazodone on depression, physicians must be made aware of the high-dose approach with trazodone and identify patients who would benefit the most. In addi- tion, there is a lack of real-world evidence on the use of trazodone in patients with PD and depression, which will be fundamental to provide more specific guidance on its use in routine clinical practice. Finally, the experts noted that there is a lack of communication between psychiatrists and neurologists, and that patients with depression and PD may be managed by psychiatrists, at least in the early stages of the disease when motor symptoms are absent or minimal. Enhanced communication between these professionals is needed and a multidisciplinary approach should be favored to organize and provide comprehensive care for both motor and non-motor symptoms [41].

  Trazodone for management of depression in Parkinson’s disease: expert opinion and proposal for a treatment algorithm · 2026 · DOI

• This study has some limitations. First, the sample size was rela- tively small, which might weaken the statistical power, although our sample size met the requirements for this study. Large-scale multi- center studies and long-term cohort studies are still recommended to verify the results. Second, this study lacked histopathological confir- mation, which was a limitation of every study that relied on clinical diagnosis (Charlotte et al., 2018). We included only typical clinical cases to minimize this limitation as much as possible. Third, the sequence of three tasks was fixed (TUG test–Cognitive Load Test– Endogenous Beat Test), and a learning effect could not be excluded. However, this influence seemed to be very limited, as there was no tendency of improvement observed in the Cognitive Load Test and the Endogenous Beat Test compared to the TUG test.

  Potential for distinguishing the parkinsonian subtype of multiple system atrophy from Parkinson’s disease: a three-dimensional gait analysis study · 2026 · DOI

• Cross-species models remain to be crucial in expanding our knowledge of PD, despite the difficulties involved in simulating complicated human diseases.

  Comparative molecular signatures of neuroprotection in Parkinson’s disease across zebrafish and naked mole rat models · 2026 · DOI

• Simple brain architecture, short lifespan Difficult maintenance, long generational time Likhar and Warke Discover Neuroscience (2026) 21:37 Page 7 of 15 A distinguishing feature of zebrafish is their innate capacity for cellular regeneration and neurogenesis, including the restoration of dopaminergic neurons, which are critically affected in PD [25, 26]. For example, dopaminergic neurons in the olfactory bulb have been shown to regenerate to baseline levels within 45 days following targeted ablation. While this regenerative ability presents a significant opportunity for studying neurorestorative mechanisms, it poses a challenge in establishing chronic PD models. Unlike mammalian systems, where neuronal loss is permanent, zebrafish can spontaneously recover from neural damage, making it difficult to sustain long-term disease progression in experimental setups. Nonetheless, this limitation simultaneously highlights the model’s unique value for investigating endogenous repair pathways with potential therapeutic implications for human neurodegenerative diseases. Furthermore, even though zebrafish are often used for behavioral study, the consistency of tests and translational validity are still difficult to achieve. Variability in experimental protocols and differences in behavioral paradigms across studies can limit reproducibility, and the extent to which zebrafish behavioral outputs accurately reflect complex human motor and non-motor symptoms of PD remains an area of ongoing investigation [12, 18]. 4 Naked mole rat as model organism Naked mole-rats (NMR, Heterocephalus glaber) have attracted interest as a comparative model for human neurodegenerative diseases due to their exceptional longevity and health span. Rather than serving as a direct disease model for PD, NMRs provide a valuable comparative framework for investigating biological mechanisms associated with neural resilience and longevity. These rodents live over 30 years—roughly 8 to 10 times longer than similarly sized mice—and maintain normal activity, cognition, and physiology deep into advanced age [8, 9]. Unlike conventional lab rodents whose lifespans are approximately 3–4 years and display progressive age-associated decline, NMRs show minimal evidence of senescence across multiple physiological systems [8, 9]. NMRs differ from conventional mammalian models in a number of biological aspects. These include prolonged cellular maintenance processes, delayed aging, and maintained neural integrity throughout life. These properties make them particularly beneficial for understanding mechanisms that may encourage neural resistance against age-related neurodegeneration. Key biological traits relevant to neurodegeneration research are summarized in Table 2.

  Comparative molecular signatures of neuroprotection in Parkinson’s disease across zebrafish and naked mole rat models · 2026 · DOI

• Future studies could explore the integration of such imaging inputs as comple- mentary tracks, improving the multimodal features which can potentially enrich the diagnostic representation. Additionally, the scalability of the system is limited by the increased use of computational resources for quantum cir- cuits.

  A quantum–classical dual-track deep learning network for explainable Parkinson’s disease classification · 2026 · DOI

• The paper did not compare the diagnostic utility of the multimodal QSM-MRS machine learning approach against conventional clinical diagnostic criteria or single-modality models (QSM-only or MRS-only), limiting assessment of the added clinical value of integrating both neuroimaging and spectroscopy biomarkers for early Parkinson's disease detection.

  Quantitative susceptibility mapping and MRS-based multimodal machine learning for early Parkinson’s disease classification · 2026 · DOI

Most-cited papers in Parkinson's Disease Mechanisms and Treatments

• Diagnosis and Treatment of Parkinson Disease · JAMA · 2020 · 2,659 citations
• Pathological α-Synuclein Transmission Initiates Parkinson-like Neurodegeneration in Nontransgenic Mice · Science · 2012 · 2,381 citations
• Mutations in the <i>DJ-1</i> Gene Associated with Autosomal Recessive Early-Onset Parkinsonism · Science · 2003 · 2,351 citations
• Pharmacological Treatment of Parkinson Disease · JAMA · 2014 · 1,301 citations
• Description of Parkinson's Disease as a Clinical Syndrome · Annals of the New York Academy of Sciences · 2003 · 770 citations
• Two Conceptions of Judicial Integrity: Traditional and Perfectionist Approaches to Issues of Morality and Social Justice · Notre Dame journal of law, ethics & public policy · 2012 · 575 citations
• An update on the diagnosis and treatment of Parkinson disease · Canadian Medical Association Journal · 2016 · 381 citations
• Neuroinflammation and α-Synuclein Dysfunction Potentiate Each Other, Driving Chronic Progression of Neurodegeneration in a Mouse Model of Parkinson’s Disease · Environmental Health Perspectives · 2011 · 318 citations
• The Frequency of Idiopathic Parkinson's Disease by Age, Ethnic Group, and Sex in Northern Manhattan, 1988–1993 · American Journal of Epidemiology · 1995 · 258 citations
• Parkinson's disease and exposure to infectious agents and pesticides and the occurrence of brain injuries: role of neuroinflammation. · Environmental Health Perspectives · 2003 · 229 citations

Most recent work

• Ultrastructural diversity and subcellular organization of nigral Lewy pathology in Parkinson's disease · bioRxiv · 2026
• Network analysis of α-synuclein pathology progression reveals p21-activated kinases as regulators of vulnerability · bioRxiv · 2026
• Investigation of Disease-Relevant Lysine Acetylation Sites in α-Synuclein Enabled by Non-canonical Amino Acid Mutagenesis · bioRxiv · 2026
• Sex and genotype influence the disruption of circulating NMDAR-related amino acids in patients with Parkinson's disease · medRxiv · 2026
• Discovery of Sexual Dimorphism in the Serum Metabolome of Parkinson's Disease Patients Harboring Rare Genetic Variants with Uncertain Pathogenicity. · medRxiv · 2026
• Riemannian Tensor Analysis Identifies a Bifurcation State in the Single-Cell Transcriptomic Landscape of Parkinson's Disease · bioRxiv · 2026
• Discovery of Potent, Selective, CNS-Penetrant Macrocyclic LRRK2 Inhibitors for the Treatment of Parkinson’s Disease · Journal of Medicinal Chemistry · 2026
• Adaptation of α-synuclein fibrils following multiple system atrophy transmission to mice · bioRxiv · 2026
• In-cell cryo-electron tomography reveals differential effects of type I and type II kinase inhibitors on LRRK2 filament formation and microtubule association · bioRxiv · 2026
• Longitudinal changes of iron in the substantia nigra of early-stage Parkinson's disease · medRxiv · 2026

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