Carotid Body Resection Prevents Short-Term Spatial Memory Decline in Prediabetic Rats Without Changing Insulin Signaling in the Hippocampus and Prefrontal Cortex.

Individuals who develop type 2 diabetes (T2D) at an early age are at higher risk of developing neurodegenerative disorders such as Alzheimer's and Parkinson's disease. A shared dysfunctional characteristic between T2D and these neurodegenerative disorders is insulin resistance. Recently, it was shown that prediabetes animals and patients exhibited increased carotid body (CB) activity.

Unveiling new secrets in Parkinson's disease: The glycatome.

We are witnessing a considerable increase in the incidence of Parkinson's disease (PD), which may be due to the general ageing of the population. While there is a plethora of therapeutic strategies for this disease, they still fail to arrest disease progression as they do not target and prevent the neurodegenerative process. The identification of disease-causing mutations allowed researchers to better dissect the underlying causes of this disease, highlighting, for example, the pathogenic role of alpha-synuclein.

Glycation modulates glutamatergic signaling and exacerbates Parkinson's disease-like phenotypes.

Alpha-synuclein (aSyn) is a central player in the pathogenesis of synucleinopathies due to its accumulation in typical protein aggregates in the brain. However, it is still unclear how it contributes to neurodegeneration. Type-2 diabetes mellitus is a risk factor for Parkinson's disease (PD).

Dysmetabolism and Neurodegeneration: Trick or Treat?

Accumulating evidence suggests the existence of a strong link between metabolic syndrome and neurodegeneration. Indeed, epidemiologic studies have described solid associations between metabolic syndrome and neurodegeneration, whereas animal models contributed for the clarification of the mechanistic underlying the complex relationships between these conditions, having the development of an insulin resistance state a pivotal role in this relationship. Herein, we review in a concise manner the association between metabolic syndrome and neurodegeneration.

Insulin-degrading enzyme: an ally against metabolic and neurodegenerative diseases.

Insulin-degrading enzyme (IDE) function goes far beyond its known proteolytic role as a regulator of insulin levels. IDE has a wide substrate promiscuity, degrading several proteins such as amyloid-β peptide, glucagon, islet amyloid polypeptide (IAPP), and insulin-like growth factors, which have diverse physiological and pathophysiological functions. Importantly, IDE plays other non-proteolytic functions such as: a chaperone/dead-end chaperone, an E1-ubiquitin activating enzyme, and a proteasome modulator.

The Neuroprotective Action of Amidated-Kyotorphin on Amyloid β Peptide-Induced Alzheimer's Disease Pathophysiology.

Kyotorphin (KTP, l-tyrosyl-l-arginine) is an endogenous dipeptide initially described to have analgesic properties. Recently, KTP was suggested to be an endogenous neuroprotective agent, namely for Alzheimer's disease (AD). In fact, KTP levels were shown to be decreased in the cerebrospinal fluid of patients with AD, and recent data showed that intracerebroventricular (i.

Hsp27 reduces glycation-induced toxicity and aggregation of alpha-synuclein.

α-synuclein (aSyn) is a major player in Parkinson's disease and a group of other disorders collectively known as synucleinopathies, but the precise molecular mechanisms involved are still unclear. aSyn, as virtually all proteins, undergoes a series of posttranslational modifications during its lifetime, which can affect its biology and pathobiology. We recently showed that glycation of aSyn by methylglyoxal (MGO) potentiates its oligomerization and toxicity, induces dopaminergic neuronal cell loss in mice, and affects motor performance in flies.

Extracellular aggregated alpha synuclein primarily triggers lysosomal dysfunction in neural cells prevented by trehalose.

Cell-to-cell propagation of aggregated alpha synuclein (aSyn) has been suggested to play an important role in the progression of alpha synucleinopathies. A critical step for the propagation process is the accumulation of extracellular aSyn within recipient cells. Here, we investigated the trafficking of distinct exogenous aSyn forms and addressed the mechanisms influencing their accumulation in recipient cells.

Alpha-Synuclein Glycation and the Action of Anti-Diabetic Agents in Parkinson's Disease.

Parkinson's disease (PD) is a neurodegenerative disorder with complex etiology and variable pathology. While a subset of cases is associated with single-gene mutations, the majority originates from a combination of factors we do not fully understand. Thus, understanding the underlying causes of PD is indispensable for the development of novel therapeutics.

Posttranslational modifications of blood-derived alpha-synuclein as biochemical markers for Parkinson's disease.

Parkinson's disease (PD) is a progressive neurodegenerative disorder known for the typical motor features associated. Pathologically, it is characterized by the intracellular accumulation of alpha-synuclein (aSyn) in Lewy bodies and Lewy neurites. Currently, there are no established biochemical markers for diagnosing or for following disease progression, a major limitation for the clinical practice.

α-synuclein interacts with PrP to induce cognitive impairment through mGluR5 and NMDAR2B.

Synucleinopathies, such as Parkinson's disease and dementia with Lewy bodies, are neurodegenerative disorders that are characterized by the accumulation of α-synuclein (aSyn) in intracellular inclusions known as Lewy bodies. Prefibrillar soluble aSyn oligomers, rather than larger inclusions, are currently considered to be crucial species underlying synaptic dysfunction. We identified the cellular prion protein (PrP) as a key mediator in aSyn-induced synaptic impairment.

Glycation potentiates α-synuclein-associated neurodegeneration in synucleinopathies.

α-Synuclein misfolding and aggregation is a hallmark in Parkinson's disease and in several other neurodegenerative diseases known as synucleinopathies. The toxic properties of α-synuclein are conserved from yeast to man, but the precise underpinnings of the cellular pathologies associated are still elusive, complicating the development of effective therapeutic strategies. Combining molecular genetics with target-based approaches, we established that glycation, an unavoidable age-associated post-translational modification, enhanced α-synuclein toxicity in vitro and in vivo, in Drosophila and in mice.

Correction: The mechanism of sirtuin 2-mediated exacerbation of alpha-synuclein toxicity in models of Parkinson disease.

[This corrects the article DOI: 10.1371/journal.pbio.

The mechanism of sirtuin 2-mediated exacerbation of alpha-synuclein toxicity in models of Parkinson disease.

Sirtuin genes have been associated with aging and are known to affect multiple cellular pathways. Sirtuin 2 was previously shown to modulate proteotoxicity associated with age-associated neurodegenerative disorders such as Alzheimer and Parkinson disease (PD). However, the precise molecular mechanisms involved remain unclear.

Glycation potentiates neurodegeneration in models of Huntington's disease.

Protein glycation is an age-dependent posttranslational modification associated with several neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. By modifying amino-groups, glycation interferes with folding of proteins, increasing their aggregation potential. Here, we studied the effect of pharmacological and genetic manipulation of glycation on huntingtin (HTT), the causative protein in Huntington's disease (HD).

Glycation in Parkinson's disease and Alzheimer's disease.

Glycation is a spontaneous age-dependent posttranslational modification that can impact the structure and function of several proteins. Interestingly, glycation can be detected at the periphery of Lewy bodies in the brain in Parkinson's disease. Moreover, α-synuclein can be glycated, at least under experimental conditions.

Adenosine A2A Receptors Modulate α-Synuclein Aggregation and Toxicity.

Abnormal accumulation of aggregated α-synuclein (aSyn) is a hallmark of sporadic and familial Parkinson's disease (PD) and related synucleinopathies. Recent studies suggest a neuroprotective role of adenosine A2A receptor (A2AR) antagonists in PD. Nevertheless, the precise molecular mechanisms underlying this neuroprotection remain unclear.

Isostructural Re(I)/(99m)Tc(I) tricarbonyl complexes for cancer theranostics.

Merging classical organic anticancer drugs with metal-based compounds in one single molecule offers the possibility of exploring new approaches for cancer theranostics, i.e. the combination of diagnostic and therapeutic modalities.

(Poly)phenols protect from α-synuclein toxicity by reducing oxidative stress and promoting autophagy.

Parkinson's disease (PD) is the most common movement neurodegenerative disorder and is associated with the aggregation of α-synuclein (αSyn) and oxidative stress, hallmarks of the disease. Although the precise molecular events underlying αSyn aggregation are still unclear, oxidative stress is known to contribute to this process. Therefore, agents that either prevent oxidative stress or inhibit αSyn toxicity are expected to constitute potential drug leads for PD.

Heat-mediated enrichment of α-synuclein from cells and tissue for assessing post-translational modifications.

α-Synuclein (α-syn) is the major component of Lewy bodies, a pathological hallmark of Parkinson's disease and other synucleinopathies. The characterization of α-syn post-translational modifications (PTMs), thought to interfere with its aggregation propensity and cellular signaling, has been limited by the availability of extraction methods of endogenous protein from cells and tissues, and by the availability of antibodies toward α-syn PTMs. Here, by taking advantage of α-syn thermostability, we applied a method to achieve high enrichment of soluble α-syn both from cultured cells and brain tissues followed by proteomics analysis.

Extracellular alpha-synuclein oligomers modulate synaptic transmission and impair LTP via NMDA-receptor activation.

Parkinson's disease (PD) is the most common representative of a group of disorders known as synucleinopathies, in which misfolding and aggregation of α-synuclein (a-syn) in various brain regions is the major pathological hallmark. Indeed, the motor symptoms in PD are caused by a heterogeneous degeneration of brain neurons not only in substantia nigra pars compacta but also in other extrastriatal areas of the brain. In addition to the well known motor dysfunction in PD patients, cognitive deficits and memory impairment are also an important part of the disorder, probably due to disruption of synaptic transmission and plasticity in extrastriatal areas, including the hippocampus.