Parkinson’s disease involves widespread neurodegeneration that extends far beyond the basal ganglia, giving rise to a diverse range of non-motor symptoms that frequently emerge before motor onset. These include autonomic dysfunction, cognitive decline, neuropsychiatric disturbances, sleep-related disorders, and sensory deficits. Here, we synthesize current evidence on the anatomical, neurochemical, and network-level mechanisms that drive these symptoms, and we examine how they shape disease progression and clinical heterogeneity. We highlight the limitations of dopamine-centric models and advocate for a framework that treats non-motor symptoms as the disorder’s primary, mechanistically distinct features. We also discuss how emerging technologies—such as multi-omic profiling, artificial intelligence, and network neuroscience—enable earlier identification, stratification of non-motor phenotypes, and the development of precision-based therapeutic strategies. Recognizing non-motor symptoms as central to Parkinson’s disease redefines how the disorder should be diagnosed, studied, and treated.

Alzheimer’s disease (AD), the most prevalent neurodegenerative disorder and the leading cause of dementia worldwide, profoundly impacts health and quality of life. While cognitive impairments—such as memory loss, attention deficits, and disorientation—predominate in AD, motor symptoms, though common, remain underexplored. These motor symptoms, including gait disturbances, reduced cardiorespiratory fitness, muscle weakness, sarcopenia, and impaired balance, are often associated with advanced stages of AD and contribute to increased mortality. Emerging evidence, however, suggests that motor symptoms may be present in earlier stages and can serve as predictive markers for AD in older adults. Despite a limited understanding of the underlying mechanisms driving these motor symptoms, several key pathways have been identified, offering avenues for further investigation. This review provides an in-depth analysis of motor symptoms in AD, discussing its progression, potential mechanisms, and therapeutic strategies. Addressing motor symptoms alongside cognitive decline may enhance patient functionality, improve quality of life, and support more comprehensive disease management strategies.

The α-synucleinopathies constitute a subset of neurodegenerative disorders, of which Parkinson’s disease (PD) is the most common worldwide, characterized by the accumulation of misfolded α-synuclein in the cytoplasm of neurons, which spreads in a prion-like manner to anatomically interconnected brain areas. However, it is not clear how α-synucleinopathy triggers neurodegeneration. We recently developed a rat model through a single intranigral administration of the neurotoxic β-sitosterol β-D-glucoside (BSSG), which produces α-synucleinopathy. In this model, we aimed to evaluate the temporal pattern of levels in oxidative and nitrosative stress and mitochondrial complex I (CI) dysfunction and how these biochemical parameters are associated with neurodegeneration in different brain areas with α-synucleinopathy (Substantia nigra pars compacta, the striatum, in the hippocampus and the olfactory bulb, where α-syn aggregation spreads). Interestingly, an increase in oxidative stress and mitochondrial CI dysfunction accompanied neurodegeneration in those brain regions. Furthermore, in silico analysis suggests a high-affinity binding site for BSSG with peroxisome proliferator-activated receptors (PPAR) alpha (PPAR-α) and gamma (PPAR-γ). These findings will contribute to elucidating the pathophysiological mechanisms associated with α-synucleinopathies and lead to the identification of new early biomarkers and therapeutic targets.

Parkinson’s disease (PD) is the most common α-synucleinopathy worldwide. The pathognomonic hallmark of PD is the misfolding and propagation of the α-synuclein (α-syn) protein, observed in post-mortem histopathology. It has been hypothesized that α-synucleinopathy triggers oxidative stress, mitochondrial dysfunction, neuroinflammation, and synaptic dysfunction, leading to neurodegeneration. To this date, there are no disease-modifying drugs that generate neuroprotection against these neuropathological events and especially against α-synucleinopathy. Growing evidence suggests that peroxisome proliferator-activated receptor (PPAR) agonists confer neuroprotective effects in PD, however, whether they also confer an anti-α-synucleinopathy effect is unknown. Here we analyze the reported therapeutic effects of PPARs, specifically the gamma isoform (PPARγ), in preclinical PD animal models and clinical trials for PD, and we suggest possible anti-α-synucleinopathy mechanisms acting downstream from these receptors. Elucidating the neuroprotective mechanisms of PPARs through preclinical models that mimic PD as closely as possible will facilitate the execution of better clinical trials for disease-modifying drugs in PD.

Whether neuroinflammation leads to dopaminergic nigrostriatal system neurodegeneration is controversial. We addressed this issue by inducing acute neuroinflammation in the substantia nigra (SN) with a single local administration (5 µg/2 µL saline solution) of lipopolysaccharide (LPS). Neuroinflammatory variables were assessed from 48 h to 30 days after the injury by immunostaining for activated microglia (Iba-1 +), neurotoxic A1 astrocytes (C3 + and GFAP +), and active caspase-1. We also evaluated NLRP3 activation and Il-1β levels by western blot and mitochondrial complex I (CI) activity. Fever and sickness behavior was assessed for 24 h, and motor behavior deficits were followed up until day 30. On this day, we evaluated the cellular senescence marker β-galactosidase (β-Gal) in the SN and tyrosine hydroxylase (TH) in the SN and striatum. After LPS injection, Iba-1 (+), C3 (+), and S100A10 (+) cells were maximally present at 48 h and reached basal levels on day 30. NLRP3 activation occurred at 24 h and was followed by a rise of active caspase-1 (+), Il-1β, and decreased mitochondrial CI activity until 48 h. A significant loss of nigral TH (+) cells and striatal terminals was associated with motor deficits on day 30. The remaining TH (+) cells were β-Gal (+), suggesting senescent dopaminergic neurons. All the histopathological changes also appeared on the contralateral side. Our results show that unilaterally LPS-induced neuroinflammation can cause bilateral neurodegeneration of the nigrostriatal dopaminergic system and are relevant for understanding Parkinson’s disease (PD) neuropathology.

Parkinson’s disease (PD) is characterized by four pathognomonic hallmarks: (1) motor and non-motor deficits; (2) neuroinflammation and oxidative stress; (3) pathological aggregates of the α-synuclein (α-syn) protein; (4) neurodegeneration of the nigrostriatal system. Recent evidence sustains that the aggregation of pathological α-syn occurs in the early stages of the disease, becoming the first trigger of neuroinflammation and subsequent neurodegeneration. Thus, a therapeutic line aims at striking back α-synucleinopathy and neuroinflammation to impede neurodegeneration. Another therapeutic line is restoring the compromised dopaminergic system using neurotrophic factors, particularly the glial cell-derived neurotrophic factor (GDNF). Preclinical studies with GDNF have provided encouraging results but often lack evaluation of anti-α-syn and anti-inflammatory effects. In contrast, clinical trials have yielded imprecise results and have reported the emergence of severe side effects. Here, we analyze the discrepancy between preclinical and clinical outcomes, review the mechanisms of the aggregation of pathological α-syn, including neuroinflammation, and evaluate the neurorestorative properties of GDNF, emphasizing its anti-α-syn and anti-inflammatory effects in preclinical and clinical trials.