Parkinson’s disease (PD) is an incurable neurodegenerative disease that is rarely diagnosed at an early stage. Although the understanding of PD-related mechanisms has greatly improved over the last decade, the diagnosis of PD is still based on neurological examination through the identification of motor symptoms, including bradykinesia, rigidity, postural instability, and resting tremor. The early phase of PD is characterized by subtle symptoms with a misdiagnosis rate of approximately 16–20%. The difficulty in recognizing early PD has implications for the potential use of novel therapeutic approaches. For this reason, it is important to discover PD brain biomarkers that can indicate early dopaminergic dysfunction through their changes in body fluids, such as saliva, urine, blood, or cerebrospinal fluid (CSF). For the CFS-based test, the invasiveness of sampling is a major limitation, whereas the other body fluids are easier to obtain and could also allow population screening. Following the identification of the crucial role of alpha-synuclein (α-syn) in the pathology of PD, a very large number of studies have summarized its changes in body fluids. However, methodological problems have led to the poor diagnostic/prognostic value of this protein and alternative biomarkers are currently being investigated. The aim of this paper is therefore to summarize studies on protein biomarkers that are alternatives to α-syn, particularly those that change in nigrostriatal areas and in biofluids, with a focus on blood, and, eventually, saliva and urine.

A disturbed balance between excitation and inhibition (E/I balance) is increasingly recognized as a key driver of neurodegeneration in multiple sclerosis (MS), a chronic inflammatory disease of the central nervous system. To understand how chronic hyperexcitability contributes to neuronal loss in MS, we transcriptionally profiled neurons from mice lacking inhibitory metabotropic glutamate signaling with shifted E/I balance and increased vulnerability to inflammation-induced neurodegeneration. This revealed a prominent induction of the nuclear receptor NR4A2 in neurons. Mechanistically, NR4A2 increased susceptibility to excitotoxicity by stimulating continuous VGF secretion leading to glycolysis-dependent neuronal cell death. Extending these findings to people with MS (pwMS), we observed increased VGF levels in serum and brain biopsies. Notably, neuron-specific deletion of Vgf in a mouse model of MS ameliorated neurodegeneration. These findings underscore the detrimental effect of a persistent metabolic shift driven by excitatory activity as a fundamental mechanism in inflammation-induced neurodegeneration.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by a progressive degeneration in the neurons of the frontal cortex, spinal cord, and brainstem, altering the correct release of neurotransmitters. The disease affects every muscle in the body and could cause death three to five years after symptoms first occur. There is currently no efficient treatment to stop the disease’s progression. The lack of identification of potential therapeutic strategies is a consequence of the delayed diagnosis due to the absence of accurate ALS early biomarkers. Indeed, neurotransmitters altered in ALS are not measurable in body fluids at quantities that allow for testing, making their use as diagnostic tools a challenge. Contrarily, neuroproteins and neuropeptides are chemical messengers produced and released by neurons, and most of them have the potential to enter bodily fluids. To find out new possible ALS biomarkers, the research of neuropeptides and proteins is intensified using mass spectrometry and biochemical-based assays. Neuropeptides derived from the proVGF precursor protein act as signaling molecules within neurons. ProVGF and its derived peptides are expressed in the nervous and endocrine systems but are also widely distributed in body fluids such as blood, urine, and cerebrospinal fluid, making them viable options as disease biomarkers. To highlight the proVGF and its derived peptides’ major roles as ALS diagnostic biomarkers, this review provides an overview of the VGF peptide alterations in spinal cord and body fluids and outlines the limitations of the reported investigations.

Background: In Parkinson’s disease (PD), changes in the brain begin before clinical symptoms. We have previously shown that VGF precursor levels were reduced in a presymptomatic PD animal model. Objectives: In the present study, we investigated whether two VGF precursor-derived products, namely NAPP-129 protein and TLQP-62 peptide, also exhibit alterations using the same PD animal model. Methods: Specifically, rats were unilaterally injected in the substantia nigra with a viral vector overexpressing green fluorescent protein (N = 12) or α-synuclein (N = 13), the latter resulting in mild dopaminergic alterations without overt motor deficits. Results: NAPP-129 and TLQP-62 were investigated in the substantia nigra, striatum, and plasma by Western blotting or immunoassays using specific antibodies against NAPP and TLQP sequences, alongside other NERP-1- and AQEE-related products. Plasma samples of a Huntington’s disease mouse model were also analyzed. We found reductions in NAPP-129 and TLQP-62 levels in the substantia nigra along with a decrease in NAPP- and TLQP-like plasma immunoreactivity in α-synuclein-overexpressed rats, while the striatum was not affected. NERP-1- and AQEE-related products were not altered. No changes were found in the Huntington’s disease model. Conclusions: These findings indicate that NAPP-129 and TLQP-62 may enhance the sensitivity and specificity of biomarker-based strategies for PD.